HER2 mediates clinical resistance to the KRASG12C inhibitor sotorasib, which is overcome by co-targeting SHP2

Introduction: Mutant Ras guanosine triphosphate hydrolases (GTPases) are key oncogenic drivers in many cancers. The KRAS^G12C variant has recently become targetable by a new drug class specifically locking KRAS^G12C in its inactive guanosine diphosphate (GDP)-bound state. Clinical activity was demonstrated in patients with advanced lung cancers harbouring KRAS^G12C mutations but was limited by the development of resistance.

Methods: A biopsy from progressing lung Cancer of a patient treated with the KRAS^G12C inhibitor sotorasib was obtained, and the underlying resistance factors were analysed. Mechanistic studies were performed in vitro and in vivo to uncover strategies to overcome resistance to KRAS^G12C inhibition.

Results: We demonstrated acquisition of HER2 copy number gain and KRAS^G12C mutation retention in the post-progression biopsy. To explore HER2 gain as the relevant resistance mechanism, we generated KRAS^G12C lung Cancer models overexpressing HER2. MAPK pathway signalling remained active despite KRAS^G12C inhibitor treatment. Combined pharmacological inhibition of KRAS^G12C and SHP2 synergistically overcame HER2-mediated resistance in vitro and in vivo.

Conclusions: These findings establish HER2 copy number gain as a clinically relevant mechanism of resistance to pharmacological KRAS^G12C inhibition that can be overcome by co-targeting SHP2.