SHP2 inhibition mitigates adaptive resistance to MEK inhibitors in KRAS-mutant gastric cancer through the suppression of KSR1 activity

Despite the promising antitumor activity of RAF/MEK inhibitors for RAS-driven cancers, not all patients respond to these therapies. Adaptive resistance has been reported as a major culprit in non-responders, which can be reversed by SHP2 inhibitors (SHP2is) in multiple cancer cells; however, the underlying mechanisms remain unknown. In this study, we found that KRAS-mutant gastric cancer cells respond to MEK inhibitors (MEKis) with adaptive resistance. Markedly, SHP2 activation accompanied by ERK signaling restoration in MEKi-treated cells, and a MEKi and SHP2i combination had a synergistic effect on downstream signaling blockade. In vivo, SHP099 combined with AZD6244 (selumetinib) was highly efficacious for the treatment of xenografts. Mechanistically, SHP2 was found to interact with the scaffold protein KSR1 through its protein tyrosine phosphatase domain. KSR1 knockdown sensitized cells to AZD6244, whereas a KSR1 activating mutation (S269A) diminished the synergistic anti-proliferative effect of SHP2i and MEKi. Interestingly, activated SHP2, during adaptive resistance to MEKis, impaired the interaction with KSR1, activating KSR1 to promote MAPK signaling. In conclusion, SHP2 promotes adaptive resistance to MEKis by activating KSR1; selumetinib combined with SHP099 might be an available therapeutic strategy for KRAS-mutant gastric cancers.