SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Adaptive resistance to MEK inhibitors (MEKi) is a major challenge in cancer therapy, often driven by receptor tyrosine kinase (RTK) signaling.
• SHP2 phosphatase is a critical node in RTK-mediated RAS/ERK pathway activation and a potential target to overcome resistance.

Purpose of the Study:

• To investigate the therapeutic potential of combining a SHP2 inhibitor (SHP099) with a MEK inhibitor (MEKi) to overcome adaptive resistance in cancer.
• To elucidate the mechanism by which SHP099/MEKi combination therapy inhibits cancer cell proliferation and tumor growth.

Main Methods:

• In vitro proliferation assays using cancer cell lines treated with SHP099 and/or MEKi.
• In vivo efficacy studies in xenograft and genetically engineered mouse models of various cancers.
• Molecular analyses including PTPN11 knockdown, mutant PTPN11 expression, and assessment of RAS/ERK pathway signaling.

Main Results:

• SHP099 combined with MEKi effectively inhibited proliferation of multiple cancer cell lines.
• The combination therapy demonstrated high efficacy in preclinical models of KRAS-mutant pancreas, lung, and ovarian cancers, as well as wild-type RAS triple-negative breast cancer.
• SHP099 blocked MEKi-induced reactivation of the RAS/ERK pathway by inhibiting KRAS activation and downstream signaling.

Conclusions:

• SHP2 inhibition in combination with MEKi is a promising strategy to prevent and overcome adaptive resistance in diverse malignancies.
• This combination therapy targets both mutant and wild-type RAS-driven cancers, highlighting its broad therapeutic potential.