Noel Warfel, Ph.D.

Non-small cell lung cancers (NSCLC) rapidly become resistant to therapy. Nrf2 is a gene that contributes to NSCLC progression and the onset of resistance to therapy. The protein KEAP1 keeps Nrf2 levels low, but in more than half of NSCLCs, mutations disrupt the function of KEAP1. Nrf2 activation represents a promising target for therapy. We recently discovered that enzymes called PIM kinases control the activation of Nrf2. PIM inhibitors can block Nrf2 activity independent of KEAP1. The goal of this research is to determine how PIM inhibitors inactivate Nrf2 in KEAP1-mutant tumors and to test the efficacy of PIM inhibitors in combination with currently approved therapies in NSCLC. PIM inhibitors have entered clinical trial testing and our findings could quickly impact patient care.

Update: In the first year of this award, we demonstrated that PIM kinase inhibitors effectively reduce Nrf2 signaling in KEAP1-deficient cell lines, representing a novel, effective approach to suppress Nrf2 activity. Treatment with PIM inhibitors overcomes Nrf2-driven therapeutic resistance to FDA-approved chemotherapies in NSCLC cell lines. Future studies will examine the mechanisms by which PIM controls Nrf2 and will test a treatment strategy of combining PIM inhibitors with chemotherapy in xenograft (surgical graft of tissue from one species to another species) and PDX (tumor tissue that has been taken from a patient and implanted into mice) models of KEAP1-deficient NSCLC.