2022 World Conference on Lung Cancer (ePosters)-EP16.03-004. Targeting SHP2 Reverts Oncogenic Mediated Resistance to KRAS-G12C Inhibition

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In a study published in the European Journal of Cancer, researchers found that the combination of the KRASG12C inhibitor sotorasib and the SHP2 inhibitor TNO155 synergistically inhibits cell proliferation and clonal outgrowth in HER2-overexpressing KRASG12C cells. This demonstrates that inhibiting SHP2 can restore sensitivity to the KRASG12C inhibitor. The study also showed that HER2 overexpression in established KRASG12C cancer cell lines leads to resistance to sotorasib, while KRASG12S-mutated cells did not respond to sotorasib regardless of HER2 status.<br /><br />The researchers further investigated the role of HER2 in resistance to sotorasib by overexpressing HER2 protein in lung cancer cell lines with different KRAS genotypes. They found that HER2 overexpression significantly reduced sensitivity to sotorasib in KRASG12C models, but not in KRASG12S mutant cells. In resistant cells, MAPK signaling remained active despite sotorasib treatment. However, the combination of TNO155 and sotorasib synergistically overcame HER2-mediated resistance in vitro and in vivo.<br /><br />In animal models, the combined treatment of sotorasib and TNO155 effectively controlled the growth of xenograft tumors from KRASG12C-positive cells overexpressing HER2. The reduced tumor burden was maintained even beyond continuous drug administration, resulting in prolonged survival of the mice.<br /><br />The study concludes that HER2 gain is a clinically relevant off-target resistance mechanism to KRASG12C inhibition, which can be overcome by co-targeting SHP2. This finding provides a rationale for combined targeting of KRASG12C and SHP2 in clinical settings.

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Alicia Isabell Tüns

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Speaker Alicia Isabell Tüns

Topic Tumour Biology and Biomarkers - Molecular Profiling and Targeted Therapies

Keywords

study

KRASG12C inhibitor

sotorasib

SHP2 inhibitor

cell proliferation

HER2 overexpression

resistance to sotorasib

combination therapy

animal models

HER2 gain