173 (PB053) - Combination of KRASG12C(ON) and SHP2 inhibitors overcomes adaptive resistance and enhances anti-tumour immunity

Abstract

Background: Oncogenic mutations in KRAS are a major cause of non-small cell lung cancer (NSCLC) and are associated with poor prognosis. Clinical use and approval of KRASG12C mutant-specific inhibitors, targeting the GDP-bound inactive (OFF) state, have shown promising results in KRASG12C-mutant NSCLC patients. However, inevitably therapy resistance occurs, and responses are short-lived. Several resistance mechanisms have been described, including upstream pathway reactivation and occurrence of secondary RAS pathway mutations.