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

OBJECTIVES

Wild type RAS (RAS) suppresses the function of oncogenic RAS mutants (RAS) in laboratory models. Loss of RAS, 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 cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RAS 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 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 LAKR, including combination strategies involving clinical KRAS and FASN inhibitors.

RESULTS

24 % of patients with KRAS LUAD showed LAKR. KRAS LAKR cases had a median survival of 16 vs. 30 months in KRAS non-LAKR (p =  0.017) and LAKR was independently associated with death in this cohort (p =  0.011). We also found that KRAS LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRAS 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 inhibitor MRTX849 in LUAD cells with KRAS and LAKR, including an in vivo trial using a xenograft model.

CONCLUSIONS

LAKR in KRAS cancers may represent an independent negative prognostic factor for patients with KRAS LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRAS and FASN inhibitors in patients with KRAS LAKR is warranted.