Loss of wild type KRAS in KRASMUT lung adenocarcinoma is associated with cancer mortality and confers sensitivity to FASN inhibitors

Abstract

ObjectivesWild type RAS (RASWT) suppresses the function of oncogenic RAS mutants (RASMUT) in laboratory models. Loss of RASWT, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RASMUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RASMUT cancers is attractive as a potential biomarker for targeted therapy. Materials and methodsWe evaluated for associations between LAKR and cancer mortality in patients with KRASMUT lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRASMUT LAKR, including combination strategies involving clinical KRASG12C and FASN inhibitors. Results24 % of patients with KRASMUT LUAD showed LAKR. KRASMUT LAKR cases had a median survival of 16 vs. 30 months in KRASMUT non-LAKR (p = 0.017) and LAKR was independently associated with death in this cohort (p = 0.011). We also found that KRASMUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRASMUT LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRASG12C inhibitor MRTX849 in LUAD cells with KRASG12C and LAKR, including an in vivo trial using a xenograft model. ConclusionsLAKR in KRASMUT cancers may represent an independent negative prognostic factor for patients with KRASMUT LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRASG12C and FASN inhibitors in patients with KRASG12C LAKR is warranted.