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

Objectives: Wild type RAS (RAS^WT) suppresses the function of oncogenic RAS mutants (RAS^MUT) in laboratory models. Loss of RAS^WT, 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 RAS^MUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RAS^MUT cancers is attractive as a potential biomarker for targeted therapy. Materials and methods: We evaluated for associations between LAKR and cancer mortality in patients with KRAS^MUT 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 KRAS^MUT LAKR, including combination strategies involving clinical KRAS^G12C and FASN inhibitors. Results: 24 % of patients with KRAS^MUT LUAD showed LAKR. KRAS^MUT LAKR cases had a median survival of 16 vs. 30 months in KRAS^MUT non-LAKR (p = 0.017) and LAKR was independently associated with death in this cohort (p = 0.011). We also found that KRAS^MUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRAS^MUT 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 KRAS^G12C inhibitor MRTX849 in LUAD cells with KRAS^G12C and LAKR, including an in vivo trial using a xenograft model. Conclusions: LAKR in KRAS^MUT cancers may represent an independent negative prognostic factor for patients with KRAS^MUT LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRAS^G12C and FASN inhibitors in patients with KRAS^G12C LAKR is warranted.