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    Association details:
    Biomarker:HER-2 overexpression + KRAS G12C
    Cancer:Non Small Cell Lung Cancer
    Drug:Lumakras (sotorasib) (KRAS G12C inhibitor) +
    batoprotafib (TNO155) (PTPN11 inhibitor)
    Direction:Sensitive
    Evidence:
    Evidence Level:
    Sensitive: D – Preclinical
    Source:
    IASLC-WCLC 2022
    Title:

    EP16.03-004 - Targeting SHP2 Reverts Oncogenic Mediated Resistance to KRAS-G12C Inhibition

    Published date:
    07/12/2022
    Excerpt:
    Overexpression of HER2 significantly reduced sensitivity to sotorasib in KRAS-G12C models but not in KRAS-G12S mutant A549 cells. In resistant cells, MAPK signaling remained active despite sotorasib treatment. Combining a SHP2 inhibitor (TNO155) and sotorasib synergistically overcame HER2-mediated resistance in vitro and in vivo. Our findings introduce HER2 gain as a clinically relevant off-target resistance mechanism to KRAS-G12C inhibition that can be rescued by co-targeting SHP2.