Targeting CRTC2 reverses <i>STK11</i> mutant NSCLC tumor resistance to immunotherapy.

Abstract

Non-small cell lung cancer (NSCLC) patients with tumors harboring <i>STK11</i> mutations are resistant to standard of care anti-PD-1/PD-L1 blockade. For this patient population there are no currently available tailored treatments, underlying the critical need to discover effective therapeutic strategies. In this study, we dissected the molecular mechanisms responsible for <i>STK11</i>-mediated resistance to immune checkpoint blockade (ICB) and identified CRTC2, a coactivator of the transcription factor cAMP response element-binding protein (CREB), as a key signaling node regulating <i>Stk11</i>-dependent cell-extrinsic functions. CRTC2 deletion remodeled the immune profiles of <i>Stk11</i>-KO tumors and resensitized them to anti-PD-1 treatment, comparably to <i>Stk11</i>-proficient tumors. Mechanistically, the abrogation of the binding between CRTC2 and CREB was sufficient to restore sensitivity to immunotherapy. These findings provide critical insights into the central role of CRTC2 in modulating response to ICB and identify the disruption of CRTC2-CREB interaction as a potential therapeutic approach for this patient population.