A druggable FOXA1-Glucocorticoid receptor transcriptional axis drives tumor growth in a subset of non-small cell lung cancer
Madeline Anne Dorso, Payal T Patel, Aleksandr Pankov, Jacob A Boyer, Rajesh Kumar Soni, Isabella S. Del Priore, Omar Hayatt, Amanda Kulick, Connor J. Hagen, Elisa de Stanchina, Melissa R Junttila, Anneleen Daemen, Lori S. Friedman, Ronald C Hendrickson, Sarat ChandarlapatyAbstract
The FOXA1 pioneer factor is an essential mediator of steroid receptor function in multiple hormone dependent cancers, including breast and prostate cancers, enabling nuclear receptors such as ER and AR to activate lineage specific growth programs. FOXA1 is also highly expressed in non-small cell lung cancer (NSCLC), but whether and how it regulates tumor growth in this context is not known. Analyzing data from loss-of-function screens, we identified a subset of NSCLC tumor lines where proliferation is FOXA1-dependent. Using rapid immunoprecipitation and mass spectrometry of endogenous protein (RIME), we identified chromatin-localized interactions between FOXA1 and glucocorticoid receptor (GR) in these tumor cells. Knockdown of GR inhibited proliferation of FOXA1-dependent, but not FOXA1-independent NSCLC cells. In these FOXA1-dependent models, FOXA1 and GR cooperate to regulate gene targets involved in EGF signaling and G1-S cell cycle progression. To investigate the therapeutic potential for targeting this complex, we examined the effects of highly selective inhibitors of the GR ligand binding pocket and found that GR antagonism with ORIC-101 suppressed FOXA1/GR target expression, activation of EGF signaling, entry into the S-phase, and attendant proliferation in vitro and in vivo. Taken together, our findings point to a subset of NSCLCs harboring a dependence on the FOXA1/GR growth program and provide rationale for its therapeutic targeting.