Allosteric SHP2 inhibitors suppress lung cancer cell migration by inhibiting non-canonical activation of EphA2 via the ERK-RSK signaling pathway

Oncogenic changes in the non-canonical ERK-RSK-EphA2 axis drive migratory behavior in non-small cell lung cancer cells. However, the role of SHP2, a tyrosine phosphatase that regulates the RAS-ERK pathway, in the activation of EphA2 remains unknown. We herein demonstrated that the allosteric SHP2 inhibitors, SHP099 and TNO155, suppressed both the TNF-α- and growth factor-induced non-canonical phosphorylation of EphA2 at Ser-897 via the ERK-RSK pathway. The significant impact of SHP2 inhibitors on non-canonical EphA2 activation in lung adenocarcinoma (LUAD) cells harboring the EGFR exon 19 deletion (PC-9, HCC827), EML4-ALK rearrangement (A925L), and KRAS mutation (A549) was also examined, and the results obtained showed a reduction in cell migration in vitro and early metastatic processes in vivo. In contrast, these inhibitors did not affect the signaling pathways leading to EphA2 induced by TPA in HeLa cells or by TNF-α in A549 cells, indicating the involvement of a complex signaling network in these processes. Collectively, the present results highlight the potential of allosteric SHP2 inhibitors as agents targeting the non-canonical activation of EphA2 in LUAD cells.