Inhibition of SHP2 enhances the effects of selective receptor tyrosine kinase inhibitors in untreated preclinical models of RET-mutated thyroid cancer
SHP2 inhibition enhances the antitumor efficacy of selective RET inhibitors in RET-mutated thyroid cancer
RET rearrangements and activating point mutations are major oncogenic drivers in thyroid cancer. Although selective RET inhibitors such as selpercatinib (LOXO-292) and pralsetinib (BLU-667) induce significant clinical responses, adaptive resistance frequently arises through reactivation of MAPK signaling. The molecular mechanisms underlying sustained ERK activation in residual RET-mutated thyroid cancer cells remain incompletely defined. Here, we investigated whether SHP2 mediates adaptive ERK reactivation following RET inhibition. RET-mutated thyroid cancer cell lines (TPC-1 and TT) were treated with selective RET inhibitors alone or in combination with the SHP2 inhibitor SHP099. RET inhibition initially suppressed ERK phosphorylation and was followed by compensatory transcriptional upregulation of multiple receptor tyrosine kinases, including MET, EGFR, FGFR2, and PDGFRB, together with ERK reactivation. Pharmacologic inhibition or knockdown of SHP2 attenuated this adaptive MAPK response and sustained ERK suppression. Combined targeting of RET and SHP2 significantly reduced cell proliferation in vitro and produced marked tumor growth inhibition in a TPC-1 xenograft model without significant loss of body weight. These findings support SHP2 as an important mediator of adaptive ERK reactivation following RET inhibition. Dual blockade of RET and SHP2 produces more durable MAPK pathway suppression and enhances antitumor efficacy in the models tested, providing a rationale for further evaluation of this combination in RET-altered thyroid cancer.
These findings support SHP2 as an important mediator of adaptive ERK reactivation following RET inhibition.
Bizonyítékszint: Klinikai vizsgálat. Formális klinikai vizsgálati eredmény.
Kapcsolódó jelek
- The dual axis of tumorigenesis: MAPK and PI3K/AKT pathways in papillary thyroid carcinoma
- The molecular mechanisms and potential therapeutic implications of the crosstalk between DNA methylation and metabolic reprogramming in thyroid cancer
- Improving predicted risk of recurrence using molecular profiling in papillary thyroid cancer
- Global Burden of Thyroid Cancer in Adults Age 15‑49 Years and Its Predictions: Findings From Global Burden of Disease Study 2021
- Thyroid Cancer: Pathogenesis, Clinicopathology, Diagnosis, and Management