Induced clustering of SHP2-depleted tumor cells in vascular islands restores sensitivity to MEK/ERK inhibition.

ABSTRACT: Allosteric inhibitors of the tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) hold therapeutic promise in cancers with overactive RAS/ERK signaling, but adaptive resistance to SHP2 inhibitors may limit benefits. Here, we utilized tumor cells that proliferate similarly with or without endogenous SHP2 to explore means to overcome this growth independence from SHP2. We found that SHP2 depletion profoundly altered the output of vascular regulators, cytokines, chemokines, and other factors from SHP2 growth-resistant cancer cells. Tumors derived from inoculation of SHP2-depleted, but SHP2 growth-independent, mouse melanoma and colon carcinoma cell lines displayed a typically subverted architecture, in which proliferative tumor cells surrounding a remode

SUBMITTER: Wang Y 

PROVIDER: S-EPMC12077907 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature