HER2 mediates clinical resistance to the KRASG12C inhibitor sotorasib, which is overcome by co-targeting SHP2. (December 2021)

• Record Type: Journal Article
• Authors: Ho, Cassandra S.L.; Tüns, Alicia I.; Schildhaus, Hans-Ulrich; Wiesweg, Marcel; Grüner, Barbara M.; Hegedus, Balazs; Schuler, Martin; Schramm, Alexander; Oeck, Sebastian
• Is Part Of: European journal of cancer. Volume 159(2021)
• Page Start: 16
• Page End: 23
• Publication Date: 2021-12
• Subjects: Lung cancer -- KRASG12C inhibition -- Acquired resistance -- SHP2 inhibition; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2021.10.003
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: 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. Highlights: Clinical implementation of KRAS G12C inhibitors is a breakthrough in lung cancer care. On-target and off-target resistance are major issues limiting clinical benefit. Acquired HER2 gain is a novel clinical resistance mechanism to KRAS G12C inhibition. HER2-mediated resistance is overcome by combining KRAS and SHP2 inhibition in vivo .