Targeting ferroptosis in aggressive subtypes of lung cancer

Ohio State University, Columbus OH

Investigators

Abstract

New therapeutic strategies are urgently needed to improve outcomes for patients with STK11/KEAP1 co-mutant non-small cell lung cancer (NSCLC). We found that concurrent STK11/KEAP1 loss-of-function (LOF) predicts poor (median overall survival of only 7.3 months) prognosis in NSCLC; compared to wildtype or single mutants. STK11/KEAP1 LOF mutations dramatically enhance cell proliferation, invasive potential in vitro, and tumor growth in xenograft lung cancer models. Furthermore, NSCLC cell lines harboring co-mutation of STK11 and KEAP1 showed significant enrichment of pathways suppressing ferroptosis, and co-mutant cells were resistant to ferroptosis-mediated death. CRISPR/Cas9-based screening of these cells identified synthetic lethal interactions specific to the co-mutant state, including a crucial regulator of ferroptosis (SCD1). Our data suggest that ferroptosis is a barrier to tumorigenesis in NSCLC and STK11/KEAP1 mutations provide multimodal ferroptosis protection in co-mutant models. However, the underlying mechanisms of ferroptosis evasion, the impact on immune microenvironment; and the effectiveness of targeting ferroptosis to overcome chemotherapy and immunotherapy resistance in STK11/KEAP1 co-mutant NSCLCs still remain largely unexplored. Our overarching hypothesis is that evasion of ferroptosis is critical to the survival and proliferation of STK11/KEAP1 co-mutant NSCLCs, and therapeutic regimens that induce ferroptosis and inhibit ferroptosis evasion could be effective therapeutic strategy to overcome therapy resistance. Our objective is to delineate the mechanism and establish ferroptosis as a potential target in STK11/KEAP1 co-mutant NSCLCs, with the long-term goal of developing novel therapies for STK11/KEAP1 co-mutant NSCLCs. Aim 1 will define the molecular and immune features associated with the progression or recalcitrance of STK11/KEAP1 co-mutant NSCLCs by (1) determining the role on tumor growth, ferroptosis, metabolic landscape and immune microenvironment in preclinical models; (3) determining the tumor heterogeneity and immune microenvironment changes associated with the aggressiveness and recalcitrance of STK11/KEAP1 co-mutant NSCLC patient tumors. Aim 2 will determine how STK11 and KEAP1 individually regulate invasion, tumor growth, and ferroptosis in preclinical models. We will examine how selective loss of STK11 or KEAP1 affects downstream signaling, promotes proliferation, invasion, ferroptosis evasion, and SCD1 expression in multiple in vivo models. Aim 3 will establish the efficacy and strategy of targeting stearoyl CoA desaturase-1 (SCD1) [with ferroptosis inducers (FINs)] to overcome resistance to chemotherapy or immunotherapy in STK11/KEAP1 co-mutant NSCLCs by (1) determining the mechanisms by which SCD1 regulates tumor growth and survival in vivo; and (2) defining the effectiveness of combining SCD1 inhibition (+/-FINs) to overcome chemotherapy and immunotherapy resistance. Our study will have a significant impact on both our basic understanding of ferroptosis and our ability to target SCD1 or ferroptosis in the most recalcitrant subset of NSCLC, directly supporting the mission of the NCI.