KRAS mutations are the most common oncogenic drivers.
Sotorasib (
AMG510), a covalent inhibitor of KRASG12C, was recently approved for the treatment of KRASG12C-mutated
non-small cell lung cancer (NSCLC). However, the efficacy of
sotorasib and other KRASG12C inhibitors is limited by intrinsic resistance in
colorectal cancer (CRC) and by the rapid emergence of acquired resistance in all treated
tumors. Therefore, there is an urgent need to develop novel combination
therapies to overcome
sotorasib resistance and to maximize its efficacy. We assessed the effect of
sotorasib alone or in combination with
DT2216 (a clinical-stage BCL-XL
proteolysis targeting chimera [
PROTAC]) on KRASG12C-mutated NSCLC, CRC and
pancreatic cancer (PC) cell lines using MTS cell viability, colony formation and
Annexin-V/PI apoptosis assays. Furthermore, the therapeutic efficacy of
sotorasib alone and in combination with
DT2216 was evaluated in vivo using different
tumor xenograft models. We observed heterogeneous responses to
sotorasib alone, whereas its combination with
DT2216 strongly inhibited viability of KRASG12C tumor cell lines that partially responded to
sotorasib treatment. Mechanistically,
sotorasib treatment led to stabilization of BIM and co-treatment with
DT2216 inhibited
sotorasib-induced BCL-XL/BIM interaction leading to enhanced apoptosis in KRASG12C tumor cell lines. Furthermore,
DT2216 co-treatment significantly improved the antitumor efficacy of
sotorasib in vivo. Collectively, our findings suggest that due to
cytostatic activity, the efficacy of
sotorasib is limited, and therefore, its combination with a pro-apoptotic
agent, i.e.,
DT2216, shows synergistic responses and can potentially overcome resistance.