2. Academic Validation
  3. HER2 mediates clinical resistance to the KRASG12C inhibitor sotorasib, which is overcome by co-targeting SHP2

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

  • Eur J Cancer. 2021 Dec;159:16-23. doi: 10.1016/j.ejca.2021.10.003.
Cassandra S L Ho 1,  Alicia I Tüns 1,  Hans-Ulrich Schildhaus 2,  Marcel Wiesweg 3,  Barbara M Grüner 4,  Balazs Hegedus 5,  Martin Schuler 6,  Alexander Schramm 1,  Sebastian Oeck 1
Affiliations

Affiliations

  • 1 Laboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
  • 2 Institute of Pathology, University Hospital Essen, Essen, Germany.
  • 3 Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
  • 4 Laboratory of Molecular Tumor Pathology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany.
  • 5 Department of Thoracic Surgery, West German Cancer Center, University Medicine Essen - Ruhrlandklinik, University Duisburg-Essen, Essen, Germany.
  • 6 Laboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany; Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany.
PMID: 34715459 DOI: 10.1016/j.ejca.2021.10.003
Abstract

Introduction: Mutant Ras guanosine triphosphate hydrolases (GTPases) are key oncogenic drivers in many cancers. The KRASG12C variant has recently become targetable by a new drug class specifically locking KRASG12C in its inactive guanosine diphosphate (GDP)-bound state. Clinical activity was demonstrated in patients with advanced lung cancers harbouring KRASG12C mutations but was limited by the development of resistance.

Methods: A biopsy from progressing lung Cancer of a patient treated with the KRASG12C 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 KRASG12C inhibition.

Results: We demonstrated acquisition of HER2 copy number gain and KRASG12C mutation retention in the post-progression biopsy. To explore HER2 gain as the relevant resistance mechanism, we generated KRASG12C Lung Cancer Models overexpressing HER2. MAPK pathway signalling remained active despite KRASG12C inhibitor treatment. Combined pharmacological inhibition of KRASG12C 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 KRASG12C inhibition that can be overcome by co-targeting SHP2.

Keywords

Acquired resistance; KRAS(G12C) inhibition; Lung cancer; SHP2 inhibition.

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