Noel Andrew Warfel
- Assistant Professor, Cellular and Molecular Medicine
2004 James Madison University
- BSc., Department of Integrated Science and Technology
2004 Johns Hopkins University
- MSc., Zanvyl Kreiger School of Arts and Science
2011 University of California, San Diego
- PhD., Biomedical Sciences graduate program
2015 – present Research Assistant Professor, University of Arizona
- Department of Cellular and Molecular Medicine
2013 – 2015 Research Assistant Professor, Medical University of South Carolina
- Joint appointment in the Hollings Cancer Center and Department of Biochemistry and Molecular Biology
2011 – 2013 Postdoctoral Fellow, Penn State University, HMC Cancer Institute
- Mentor: Dr. Wafik El-Deiry
2006 – 2011 Graduate Student, University of California, San Diego
- Mentor: Dr. Alexandra C. Newton
2004 – 2006 Graduate Research Fellow, National Cancer Insititute
- Mentor: Dr. Phillip Dennis
2017 American Lung Association Lung Cancer Discovery Award
2016 American Cancer Society Research Scholar Grant
2012 - 2014 Ruth L. Kirschstein National Research Service Award
- National Cancer Institute (1F32CA174138-01)
2009 – 2011 Predoctoral Traineeship Award
- DoD Breast Cancer Research Program (BC093021)
2009 Dissertation Award, CBCRP (Declined in favor of DoD award)
2006 – 2008 Pharmacology training grant, UCSD
- NIH (5 T32 GM07752-28)
2004 – 2006 Molecular Targets and Drug Discovery Fellowship
- Joint program - NIH/Johns Hopkins University
2013 AACR-Aflac Scholar in Training Award, AACR Annual Meeting
2012 Roland K. Robins Pharmacology Dissertation Award for best thesis, UCSD
2011 AACR Scholar in Training Award, Targeting PI3K/mTOR Signalling in Cancer
2004 Honors senior project in the department of ISAT, James Madison University
2015 – present University of Arizona Cancer Biology GIDP
2008 - present American Association for Cancer Research
2002 – 2006 Golden Key International Honor Society
SUPERVISION OF STUDENTS (2015-2016)
Supervision of 3 undergraduate students: Alva Sainz (entered Yale graduate program in biology fall of 2016), Isabella Brody-Calixito, and Ian Burton.
Supervision of 1 MSc student: Ashley Suiter
Supervision of 1 PhD student: Andrea Casillas
2016 - present UA COM MMI interviewer
2012 - present Peer reviewer for Cancer Biology and Therapy and Oncotarget
2009 Reviewer for Journal of Experimental & Clinical Cancer Research
2017 Poster presentation at AACR Prostate Cancer Meeting
2017 Invited speaker at Purdue University MCMP seminar series
2016 Poster presentation at 2016 AACR Annual Meeting
2016 Utilizing PIM Kinase inhibitors to target Nrf2-driven cancers. Invited Speaker, Pharmacology seminar series, Univ. of Arizona
2015 Targeting PIM Kinases to Overcome hypoxia-mediated therapeutic resistance. Invited Speaker, Cancer Biology seminar series, Univ. of Arizona Cancer Center
2014 Poster presentation at the 2014 Hollings Cancer Center Prostate Cancer Research Retreat
2013 Poster presentation at the 2013 AACR Annual Meeting
2013 Poster presentation at the 11th PSU postdoctoral society annual event
2012 Poster presentation at the 2012 AACR Annual Meeting
2011 Poster presentation at AACR PI3K/mTOR Signaling in Cancer meeting
2010 Invited Speaker at UCSD Biomedical Sciences annual graduate retreat
2010 Poster presentation at Salk Institute meeting on Protein Phosphorylation and Cell Signaling
2010 Poster presentation at CSHL PTEN and Pathways Meeting
2009 Poster presentation at 2009 AACR Annual Meeting
2008 Poster presentation at Salk meeting on protein phosphorylation
2008 Poster presentation at Experimental Biology Annual Meeting
2007 Invited Speaker at UCSD Biomedical Sciences annual graduate retreat
2006 Poster presentation at AACR Annual Meeting
PEER REVIEWED PUBLICATIONS
- N. A. Warfel, E. R. Lepper, C. Zhang, W. D. Figg, P. A. Dennis, Importance of the stress kinase p38alpha in mediating the direct cytotoxic effects of the thalidomide analogue, CPS49, in cancer cells and endothelial cells. Clin Cancer Res 12, 3502 (2006).
- C. A. Granville, N. Warfel, J. Tsurutani, M. C. Hollander, M. Robertson, S. D. Fox, T. D. Veenstra, H. J. Issaq, R. I. Linnoila, P. A. Dennis, Identification of a highly effective rapamycin schedule that markedly reduces the size, multiplicity, and phenotypic progression of tobacco carcinogen-induced murine lung tumors. Clin Cancer Res 13, 2281 (2007).
- J. J. Gills, S. S. Castillo, C. Zhang, P. A. Petukhov, R. M. Memmott, M. Hollingshead, N. Warfel, J. Han, A. P. Kozikowski, P. A. Dennis, Phosphatidylinositol ether lipid analogues that inhibit AKT also independently activate the stress kinase, p38alpha, through MKK3/6-independent and -dependent mechanisms. J Biol Chem 282, 27020 (2007).
- J. J. Gills, J. Lopiccolo, J. Tsurutani, R. H. Shoemaker, C. J. Best, M. S. Abu-Asab, J. Borojerdi, N. A. Warfel, E. R. Gardner, M. Danish, M. C. Hollander, S. Kawabata, M. Tsokos, W. D. Figg, P. S. Steeg, P. A. Dennis, Nelfinavir, A lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo. Clin Cancer Res 13, 5183 (2007).
- J. Brognard, M. Niederst, G. Reyes, N. Warfel, A. C. Newton, Common polymorphism in the phosphatase PHLPP2 results in reduced regulation of Akt and protein kinase C. J Biol Chem 284, 15215 (2009).
- N. A. Warfel, M. Niederst, M. W. Stevens, P. M. Brennan, M. C. Frame, A. C. Newton, Mislocalization of the E3 ligase, beta-transducin repeat-containing protein 1 (beta-TrCP1), in the pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1) and Akt. J Biol Chem 286, 19777 (2011).
- N. A. Warfel, M. Niederst, A. C. Newton, Disruption of the interface between the PH and kinase domains of Akt is sufficient for hydrophobic motif site phosphorylation in the absence of mTORC2. J Biol Chem, (2011).
- N. A. Warfel, A. C. Newton, PH domain Leucine-rich Repeat Protein Phosphatase, PHLPP: a New Player in Cell Signaling. J Biol Chem, (2011).
- V.V. Prabhu, N.A. Warfel, W.S. El-Deiry, CTGF-mediated autophagy-senescence transition in tumor stroma promotes anabolic tumor growth and metastasis. Cell Cycle, (2012).
- N. A. Warfel, W. S. El-Deiry, p21WAF1 and tumourigenesis: 20 years after. Curr Opin Oncol 25, 52 (Jan, 2013).
- N.A. Warfel, N. Dolloff, Dicker D.T., J. Malysz, W. S. El-Diery, CDK1-mediated phosphorylation of Ser668 stabalizes HIF-1a to promote tumor growth. Cell Cycle (2013).
- N.A. Warfel and W.S. El-Deiry, HIF-1 Signaling in Drug Resistance to Chemotherapy. Curr Med Chem, (2014).
- N.A. Warfel and A.S. Kraft, PIM Kinase (and Akt) Biology and Signaling in Tumors. Pharmacology and Therapeutics, (2015).
- Zhang S., Zhou L., Hong B., van den Heuvel A.P., Prabhu V.V., Warfel N.A., Kline C.L., Dicker D.T., Kopelovich L., El-Deiry W.S. Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53. Cancer research, (2015)
- Song J.H., Padi S.K., Luevano L.A., Minden M.D., DeAngelo D.J., Hardiman G., Ball L.E., Warfel N.A., Kraft A.S. Insulin receptor substrate 1 is a substrate of the Pim protein kinases. Oncotarget. (2016).
- Warfel N.A*., Sainz A.G., Song J.H., Kraft A.S*. PIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species. Molecular Cancer Therapeutics. (2016). *co-corresponding authors.
- Warfel N.A. Targeting CDK4/6 to Oppose Hypoxia-Mediated Therapeutic Resistance. Cell Cycle, (2017).
- Casillas, A.L., Sainz, A.G., Toth, R.K., Singh, N., Desai, A., Kraft, A.S., and Warfel, N.A. Hypoxia-inducible PIM Kinase expression promotes resistance to anti-angiogenic agents. Clinical Cancer Research, (2018).
- Ph.D. Biomedical Sciences
- University of California, San Diego, La Jolla, California, United States
- Regulation of the PHLPP Phosphatases and Akt Signaling
- M.S. Biotechnology
- Johns Hopkins University, Baltimore, Maryland, United States
- Medical University of South Carolina (2013 - 2015)
- Penn State Hershey Cancer Institute (2011 - 2013)
- Certificate in Translational Medicine
- Eureka Institute for Translational Medicine, Spring 2019
In addition to my passion for research, I have taken advantage of the opportunity to serve as a mentor to clinical fellows, undergraduate, and graduate students. Since arriving at Univ. of Arizona, I have served as a mentor to Alva Sainz, a talented undergraduate in the UROC program. Her work will be included in two manuscripts, and she has recently been accepted into several graduate programs to study cancer biology. In addition, I had my first ABBS student, Andrea Casillas, rotate in my lab this winter. Her rotation project was to generate and characterize a somatic mutation in HIF-1 that is widely observed in clinical samples. In addition to my training, I have learned from mentoring students in my own lab. As a result, I have confidence in my ability to effectively train students in both the conceptual and technical aspects of how to study cancer biology through hypothesis driven science. I am extremely interested in serving as a mentor to train the next generation of scientist in cancer biology. In the coming year I hope to recruit a graduate student into my lab and train another undergraduate.
My laboratory concentrates on understanding the complex biological mechanisms that allow cancer cells to thrive in the hypoxic tumor microenvironment, with a focus on understanding how we can exploit such pathways to oppose the oncogenic properties of tumor hypoxia. In particular, we are currently focused on understanding how the Proviral Integration site for Moloney murine leukemia virus (PIM) kinases regulation of tumor angiogenesis and response to therapy. This research will be the first to describe a novel signaling pathway discovered in our lab in which PIM kinases control the amplitude of hypoxia-inducible factor-1 (HIF-1) signaling. Our working model places PIM kinases upstream of HIF-1 in the cellular response to hypoxia, making it a promising target for hypoxia-targeted therapy. We have developed innovative biochemical and imaging techniques to understand how aberrant PIM expression/activity impacts tumor angiogenesis and resistance to therapy in vitro and in vivo. Of particular significance, our preliminary data provide the rationale for a novel therapeutic strategy combining small molecule PIM kinase inhibitors and anti-angiogenic drugs that has the potential to change how we treat hypoxic tumors. My training is in two areas: cancer biology, focused on signal transduction, and drug development, focused on identifying and exploiting hypoxia in solid tumors; these skills remain pillars of my current research program studying prostate cancer biology and barriers to its effective treatment. My background greatly influences the approach I am currently taking to investigate the the cellular response to hypoxia, and this work will distinguish my laboratory as we pursue biological avenues that may have been overlooked by others.
Cancer BiologyCBIO 552 (Fall 2021)
Prin of Cell BiologyCMM 577 (Fall 2021)
Cell Biology of DiseaseCMM 404 (Summer I 2021)
Cell Biology of DiseaseCMM 504 (Summer I 2021)
CBIO GIDP Seminar SeriesCBIO 596H (Spring 2021)
Directed ResearchMCB 792 (Spring 2021)
DissertationCBIO 920 (Spring 2021)
ResearchCBIO 900 (Spring 2021)
Research ConferenceCBIO 695A (Spring 2021)
ThesisCMM 910 (Spring 2021)
Cancer BiologyCBIO 552 (Fall 2020)
DissertationCBIO 920 (Fall 2020)
Prin of Cell BiologyCMM 577 (Fall 2020)
Prin of Cell BiologyMCB 577 (Fall 2020)
ResearchCBIO 900 (Fall 2020)
Research ConferenceCBIO 695A (Fall 2020)
ThesisCMM 910 (Fall 2020)
Cell Biology of DiseaseCMM 504 (Summer I 2020)
Adv Topics in Cancer BiologyCBIO 553 (Spring 2020)
CBIO GIDP Seminar SeriesCBIO 596H (Spring 2020)
DissertationCBIO 920 (Spring 2020)
Research ConferenceCBIO 695A (Spring 2020)
ThesisCMM 910 (Spring 2020)
Cancer BiologyCBIO 552 (Fall 2019)
DissertationCBIO 920 (Fall 2019)
Introduction to ResearchMCB 795A (Fall 2019)
Prin of Cell BiologyCMM 577 (Fall 2019)
Prin of Cell BiologyMCB 577 (Fall 2019)
Research ConferenceCBIO 695A (Fall 2019)
ThesisCMM 910 (Fall 2019)
Cell Biology of DiseaseCMM 404 (Summer I 2019)
Cell Biology of DiseaseCMM 504 (Summer I 2019)
ThesisCMM 910 (Summer I 2019)
CBIO GIDP Seminar SeriesCBIO 596H (Spring 2019)
ResearchCBIO 900 (Spring 2019)
Research ConferenceCBIO 695A (Spring 2019)
ThesisCMM 910 (Spring 2019)
Cancer BiologyCBIO 552 (Fall 2018)
DissertationCBIO 920 (Fall 2018)
Prin of Cell BiologyCMM 577 (Fall 2018)
Prin of Cell BiologyMCB 577 (Fall 2018)
ResearchCBIO 900 (Fall 2018)
Research ConferenceCBIO 695A (Fall 2018)
Adv Topics in Cancer BiologyCBIO 553 (Spring 2018)
ResearchCBIO 900 (Spring 2018)
Research ConferenceCBIO 695A (Spring 2018)
Cancer BiologyCBIO 552 (Fall 2017)
Introduction to ResearchMCB 795A (Fall 2017)
ResearchCBIO 900 (Fall 2017)
Research ConferenceCBIO 695A (Fall 2017)
ResearchCBIO 900 (Spring 2017)
Research ConferenceCBIO 695A (Spring 2017)
ResearchCBIO 900 (Fall 2016)
Research ConferenceCBIO 695A (Fall 2016)
ThesisCMM 910 (Fall 2016)
CBIO GIDP Seminar SeriesCBIO 596H (Spring 2016)
Directed RsrchMCB 492 (Spring 2016)
- Toth, R. K., & Warfel, N. A. (2021). Targeting PIM Kinases to Overcome Therapeutic Resistance in Cancer. Molecular cancer therapeutics, 20(1), 3-10.More infoCancer progression and the onset of therapeutic resistance are often the results of uncontrolled activation of survival kinases. The proviral integration for the Moloney murine leukemia virus (PIM) kinases are oncogenic serine/threonine kinases that regulate tumorigenesis by phosphorylating a wide range of substrates that control cellular metabolism, proliferation, and survival. Because of their broad impact on cellular processes that facilitate progression and metastasis in many cancer types, it has become clear that the activation of PIM kinases is a significant driver of resistance to various types of anticancer therapies. As a result, efforts to target PIM kinases for anticancer therapy have intensified in recent years. Clinical and preclinical studies indicate that pharmacologic inhibition of PIM has the potential to significantly improve the efficacy of standard and targeted therapies. This review focuses on the signaling pathways through which PIM kinases promote cancer progression and resistance to therapy, as well as highlights biological contexts and promising strategies to exploit PIM as a therapeutic target in cancer.
- Chauhan, S. S., Toth, R. K., Jensen, C. C., Casillas, A. L., Kashatus, D. F., & Warfel, N. A. (2020). PIM kinases alter mitochondrial dynamics and chemosensitivity in lung cancer. Oncogene, 39(12), 2597-2611.More infoResistance to chemotherapy represents a major obstacle to the successful treatment of non-small-cell lung cancer (NSCLC). The goal of this study was to determine how PIM kinases impact mitochondrial dynamics, ROS production, and response to chemotherapy in lung cancer. Live-cell imaging and microscopy were used to determine the effect of PIM loss or inhibition on mitochondrial phenotype and ROS. Inhibition of PIM kinases caused excessive mitochondrial fission and significant upregulation of mitochondrial superoxide, increasing intracellular ROS. Mechanistically, we define a signaling axis linking PIM1 to Drp1 and mitochondrial fission in lung cancer. PIM inhibition significantly increased the protein levels and mitochondrial localization of Drp1, causing marked fragmentation of mitochondria. An inverse correlation between PIM1 and Drp1 was confirmed in NSCLC patient samples. Inhibition of PIM sensitized NSCLC cells to chemotherapy and produced a synergistic antitumor response in vitro and in vivo. Immunohistochemistry and transmission electron microscopy verified that PIM inhibitors promote mitochondrial fission and apoptosis in vivo. These data improve our knowledge about how PIM1 regulates mitochondria and provide justification for combining PIM inhibition with chemotherapy in NSCLC.
- Harryman, W. L., Warfel, N. A., Nagle, R. B., & Cress, A. E. (2019). The Tumor Microenvironments of Lethal Prostate Cancer. Advances in experimental medicine and biology, 1210, 149-170.More infoLocalized prostate cancer (confined to the gland) generally is considered curable, with nearly a 100% 5-year-survival rate. When the tumor escapes the prostate capsule, leading to metastasis, there is a poorer prognosis and higher mortality rate, with 5-year survival dropping to less than 30%. A major research question has been to understand the transition from indolent (low risk) disease to aggressive (high risk) disease. In this chapter, we provide details of the changing tumor microenvironments during prostate cancer invasion and their role in the progression and metastasis of lethal prostate cancer. Four microenvironments covered here include the muscle stroma, perineural invasion, hypoxia, and the role of microvesicles in altering the extracellular matrix environment. The adaptability of prostate cancer to these varied microenvironments and the cues for phenotypic changes are currently understudied areas. Model systems for understanding smooth muscle invasion both in vitro and in vivo are highlighted. Invasive human needle biopsy tissue and mouse xenograft tumors both contain smooth muscle invasion. In combination, the models can be used in an iterative process to validate molecular events for smooth muscle invasion in human tissue. Understanding the complex and interacting microenvironments in the prostate holds the key to early detection of high-risk disease and preventing tumor invasion through escape from the prostate capsule.
- Rubenstein, C. S., Gard, J. M., Wang, M., McGrath, J. E., Ingabire, N., Hinton, J. P., Marr, K. D., Simpson, S. J., Nagle, R. B., Miranti, C. K., Warfel, N. A., Garcia, J. G., Arif-Tiwari, H., & Cress, A. E. (2019). Gene Editing of α6 Integrin Inhibits Muscle Invasive Networks and Increases Cell-Cell Biophysical Properties in Prostate Cancer. Cancer research, 79(18), 4703-4714.More infoHuman prostate cancer confined to the gland is indolent (low-risk), but tumors outside the capsule are aggressive (high-risk). Extracapsular extension requires invasion within and through a smooth muscle-structured environment. Because integrins respond to biomechanical cues, we used a gene editing approach to determine if a specific region of laminin-binding α6β1 integrin was required for smooth muscle invasion both and . Human tissue specimens showed prostate cancer invasion through smooth muscle and tumor coexpression of α6 integrin and E-cadherin in a cell-cell location and α6 integrin in a cell-extracellular matrix (ECM) distribution. Prostate cancer cells expressing α6 integrin (DU145 α6WT) produced a 3D invasive network on laminin-containing Matrigel and invaded into smooth muscle both and . In contrast, cells without α6 integrin (DU145 α6KO) and cells expressing an integrin mutant (DU145 α6AA) did not produce invasive networks, could not invade muscle both and , and surprisingly formed 3D cohesive clusters. Using electric cell-substrate impedance testing, cohesive clusters had up to a 30-fold increase in normalized resistance at 400 Hz (cell-cell impedance) as compared with the DU145 α6WT cells. In contrast, measurements at 40,000 Hz (cell-ECM coverage) showed that DU145 α6AA cells were two-fold decreased in normalized resistance and were defective in restoring resistance after a 1 μmol/L S1P challenge as compared with the DU145 α6WT cells. The results suggest that gene editing of a specific α6 integrin extracellular region, not required for normal tissue function, can generate a new biophysical cancer phenotype unable to invade the muscle, presenting a new therapeutic strategy for metastasis prevention in prostate cancer. SIGNIFICANCE: This study shows an innovative strategy to block prostate cancer metastasis and invasion in the muscle through gene editing of a specific α6 integrin extracellular region.
- Toth, R. K., Tran, J. D., Muldong, M. T., Nollet, E. A., Schulz, V. V., Jensen, C. C., Hazlehurst, L. A., Corey, E., Durden, D., Jamieson, C., Miranti, C. K., & Warfel, N. A. (2019). Hypoxia-induced PIM kinase and laminin-activated integrin α6 mediate resistance to PI3K inhibitors in bone-metastatic CRPC. American journal of clinical and experimental urology, 7(4), 297-312.More infoBone-metastatic castration-resistant prostate cancer (CRPC) is lethal due to inherent resistance to androgen deprivation therapy, chemotherapy, and targeted therapies. Despite the fact that a majority of CRPC patients (approximately 70%) harbor a constitutively active PI3K survival pathway, targeting the PI3K/mTOR pathway has failed to increase overall survival in clinical trials. Here, we identified two separate and independent survival pathways induced by the bone tumor microenvironment that are hyperactivated in CRPC and confer resistance to PI3K inhibitors. The first pathway involves integrin α6β1-mediated adhesion to laminin and the second involves hypoxia-induced expression of PIM kinases. and models demonstrate that these pathways transduce parallel but independent signals that promote survival by reducing oxidative stress and preventing cell death. We further demonstrate that both pathways drive resistance to PI3K inhibitors in PTEN-negative tumors. These results provide preclinical evidence that combined inhibition of integrin α6β1 and PIM kinase in CRPC is required to overcome tumor microenvironment-mediated resistance to PI3K inhibitors in PTEN-negative tumors within the hypoxic and laminin-rich bone microenvironment.
- Casillas, A. L., Toth, R. K., Sainz, A. G., Singh, N., Desai, A. A., Kraft, A. S., & Warfel, N. A. (2018). Hypoxia-Inducible PIM Kinase Expression Promotes Resistance to Antiangiogenic Agents. Clinical cancer research : an official journal of the American Association for Cancer Research, 24(1), 169-180.More infoPatients develop resistance to antiangiogenic drugs, secondary to changes in the tumor microenvironment, including hypoxia. PIM kinases are prosurvival kinases and their expression increases in hypoxia. The goal of this study was to determine whether targeting hypoxia-induced PIM kinase expression is effective in combination with VEGF-targeting agents. The rationale for this therapeutic approach is based on the fact that antiangiogenic drugs can make tumors hypoxic, and thus more sensitive to PIM inhibitors. Xenograft and orthotopic models of prostate and colon cancer were used to assess the effect of PIM activation on the efficacy of VEGF-targeting agents. IHC and imaging were used to analyze angiogenesis, apoptosis, proliferation, and metastasis. Biochemical studies were performed to characterize the novel signaling pathway linking PIM and HIF1. PIM was upregulated following treatment with anti-VEGF therapies, and PIM1 overexpression reduced the ability of these drugs to disrupt vasculature and block tumor growth. PIM inhibitors reduced HIF1 activity, opposing the shift to a pro-angiogenic gene signature associated with hypoxia. Combined inhibition of PIM and VEGF produced a synergistic antitumor response characterized by decreased proliferation, reduced tumor vasculature, and decreased metastasis. This study describes PIM kinase expression as a novel mechanism of resistance to antiangiogenic agents. Our data provide justification for combining PIM and VEGF inhibitors to treat solid tumors. The unique ability of PIM inhibitors to concomitantly target HIF1 and selectively kill hypoxic tumor cells addresses two major components of tumor progression and therapeutic resistance. .
- Chauhan, S. S., & Warfel, N. A. (2018). Targeting PIM kinases to oppose hypoxia-mediated therapeutic resistance. Oncoscience, 5(9-10), 254-255.
- Song, J. H., Singh, N., Luevano, L. A., Padi, S. K., Okumura, K., Olive, V., Black, S. M., Warfel, N. A., Goodrich, D. W., & Kraft, A. S. (2018). Mechanisms Behind Resistance to PI3K Inhibitor Treatment Induced by the PIM Kinase. Molecular cancer therapeutics, 17(12), 2710-2721.More infoCancer resistance to PI3K inhibitor therapy can be in part mediated by increases in the PIM1 kinase. However, the exact mechanism by which PIM kinase promotes tumor cell resistance is unknown. Our study unveils the pivotal control of redox signaling by PIM kinases as a driver of this resistance mechanism. PIM1 kinase functions to decrease cellular ROS levels by enhancing nuclear factor erythroid 2-related factor 2 (NRF2)/antioxidant response element activity. PIM prevents cell death induced by PI3K-AKT-inhibitory drugs through a noncanonical mechanism of NRF2 ubiquitination and degradation and translational control of NRF2 protein levels through modulation of eIF4B and mTORC1 activity. Importantly, PIM also controls NAD(P)H production by increasing glucose flux through the pentose phosphate shunt decreasing ROS production, and thereby diminishing the cytotoxicity of PI3K-AKT inhibitors. Treatment with PIM kinase inhibitors reverses this resistance phenotype, making tumors increasingly susceptible to small-molecule therapeutics, which block the PI3K-AKT pathway.
- Toth, R. K., & Warfel, N. A. (2017). Strange Bedfellows: Nuclear Factor, Erythroid 2-Like 2 (Nrf2) and Hypoxia-Inducible Factor 1 (HIF-1) in Tumor Hypoxia. Antioxidants (Basel, Switzerland), 6(2).More infoThe importance of the tumor microenvironment for cancer progression and therapeutic resistance is an emerging focus of cancer biology. Hypoxia, or low oxygen, is a hallmark of solid tumors that promotes metastasis and represents a significant obstacle to successful cancer therapy. In response to hypoxia, cancer cells activate a transcriptional program that allows them to survive and thrive in this harsh microenvironment. Hypoxia-inducible factor 1 (HIF-1) is considered the main effector of the cellular response to hypoxia, stimulating the transcription of genes involved in promoting angiogenesis and altering cellular metabolism. However, growing evidence suggests that the cellular response to hypoxia is much more complex, involving coordinated signaling through stress response pathways. One key signaling molecule that is activated in response to hypoxia is nuclear factor, erythroid 2 like-2 (Nrf2). Nrf2 is a transcription factor that controls the expression of antioxidant-response genes, allowing the cell to regulate reactive oxygen species. Nrf2 is also activated in various cancer types due to genetic and epigenetic alterations, and is associated with poor survival and resistance to therapy. Emerging evidence suggests that coordinated signaling through Nrf2 and HIF-1 is critical for tumor survival and progression. In this review, we discuss the distinct and overlapping roles of HIF-1 and Nrf2 in the cellular response to hypoxia, with a focus on how targeting Nrf2 could provide novel chemotherapeutic modalities for treating solid tumors.
- Warfel, N. A. (2017). Targeting CDK4/6 to oppose hypoxia-mediated therapeutic resistance. Cell cycle (Georgetown, Tex.), 16(13), 1241-1242.
- Song, J. H., Padi, S. K., Luevano, L. A., Minden, M. D., DeAngelo, D. J., Hardiman, G., Ball, L. E., Warfel, N. A., & Kraft, A. S. (2016). Insulin receptor substrate 1 is a substrate of the Pim protein kinases. Oncotarget, 7(15), 20152-65.More infoThe Pim family of serine/threonine protein kinases (Pim 1, 2, and 3) contribute to cellular transformation by regulating glucose metabolism, protein synthesis, and mitochondrial oxidative phosphorylation. Drugs targeting the Pim protein kinases are being tested in phase I/II clinical trials for the treatment of hematopoietic malignancies. The goal of these studies was to identify Pim substrate(s) that could help define the pathway regulated by these enzymes and potentially serve as a biomarker of Pim activity. To identify novel substrates, bioinformatics analysis was carried out to identify proteins containing a consensus Pim phosphorylation site. This analysis identified the insulin receptor substrate 1 and 2 (IRS1/2) as potential Pim substrates. Experiments were carried out in tissue culture, animals, and human samples from phase I trials to validate this observation and define the biologic readout of this phosphorylation. Our study demonstrates in both malignant and normal cells using either genetic or pharmacological inhibition of the Pim kinases or overexpression of this family of enzymes that human IRS1S1101 and IRS2S1149 are Pim substrates. In xenograft tumor experiments and in a human phase I clinical trial, a pan-Pim inhibitor administered in vivo to animals or humans decreased IRS1S1101 phosphorylation in tumor tissues. This phosphorylation was shown to have effects on the half-life of the IRS family of proteins, suggesting a role in insulin or IGF signaling. These results demonstrate that IRS1S1101 is a novel substrate for the Pim kinases and provide a novel marker for evaluation of Pim inhibitor therapy.
- Warfel, N. A., Sainz, A. G., Song, J. H., & Kraft, A. S. (2016). PIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species. Molecular cancer therapeutics, 15(7), 1637-47.More infoIntratumoral hypoxia is a significant obstacle to the successful treatment of solid tumors, and it is highly correlated with metastasis, therapeutic resistance, and disease recurrence in cancer patients. As a result, there is an urgent need to develop effective therapies that target hypoxic cells within the tumor microenvironment. The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases represent a prosurvival pathway that is upregulated in response to hypoxia, in a HIF-1-independent manner. We demonstrate that pharmacologic or genetic inhibition of PIM kinases is significantly more toxic toward cancer cells in hypoxia as compared with normoxia. Xenograft studies confirm that PIM kinase inhibitors impede tumor growth and selectively kill hypoxic tumor cells in vivo Experiments show that PIM kinases enhance the ability of tumor cells to adapt to hypoxia-induced oxidative stress by increasing the nuclear localization and activity of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), which functions to increase the expression of antioxidant genes. Small molecule PIM kinase inhibitors prevent Nrf2 from accumulating in the nucleus, reducing the transcription of cytoprotective genes and leading to the build-up of intracellular reactive oxygen species (ROS) to toxic levels in hypoxic tumor cells. This toxic effect of PIM inhibitors can be successfully blocked by ROS scavengers, including N-acetyl cystine and superoxide dismutase. Thus, inhibition of PIM kinases has the potential to oppose hypoxia-mediated therapeutic resistance and induce cell death in the hypoxic tumor microenvironment. Mol Cancer Ther; 15(7); 1637-47. ©2016 AACR.
- Warfel, N. A., & Kraft, A. S. (2015). PIM kinase (and Akt) biology and signaling in tumors. Pharmacology & therapeutics, 151, 41-9.More infoThe initiation and progression of human cancer is frequently linked to the uncontrolled activation of survival kinases. Two such pro-survival kinases that are commonly amplified in cancer are PIM and Akt. These oncogenic proteins are serine/threonine kinases that regulate tumorigenesis by phosphorylating substrates that control the cell cycle, cellular metabolism, proliferation, and survival. Growing evidence suggests that cross-talk exists between the PIM and Akt kinases, indicating that they control partially overlapping survival signaling pathways that are critical to the initiation, progression, and metastatic spread of many types of cancer. The PI3K/Akt signaling pathway is activated in many human tumors, and it is well established as a promising anticancer target. Likewise, based on the role of PIM kinases in normal and tumor tissues, it is clear that this family of kinases represents an interesting target for anticancer therapy. Pharmacological inhibition of PIM has the potential to significantly influence the efficacy of standard and targeted therapies. This review focuses on the regulation of PIM kinases, their role in tumorigenesis, and the biological impact of their interaction with the Akt signaling pathway on the efficacy of cancer therapy.
- Zhang, S., Zhou, L., Hong, B., van den Heuvel, A. P., Prabhu, V. V., Warfel, N. A., Kline, C. L., Dicker, D. T., Kopelovich, L., & El-Deiry, W. S. (2015). Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53. Cancer research, 75(18), 3842-52.More infoThe tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or antiangiogenesis processes. Over 50% of human cancers harbor cancer-causing mutant p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 to restore a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We demonstrate that small-molecule NSC59984 not only restores wild-type p53 signaling, but also depletes mutant p53 GOF. NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin-proteasome pathway. NSC59984 restores wild-type p53 signaling via p73 activation, specifically in mutant p53-expressing colorectal cancer cells. At therapeutic doses, NSC59984 induces p73-dependent cell death in cancer cells with minimal genotoxicity and without evident toxicity toward normal cells. NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73-dependent manner in vivo. We hypothesize that specific targeting of mutant p53 may be essential for anticancer strategies that involve the stimulation of p73 in order to efficiently restore tumor suppression. Taken together, our data identify NSC59984 as a promising lead compound for anticancer therapy that acts by targeting GOF-mutant p53 and stimulates p73 to restore the p53 pathway signaling.
- Sainz, A. G., Song, J., Kraft, A., & Warfel, N. A. (2016, 07-15-2016). PIM kinase inhibitors selectively kill hypoxic cancer cells by reducing Nrf2 activity and increasing reactive oxygen species. In AACR Annual Meeting, Cancer Research, Volume 76, Issue 14.