Tumor Intrinsic Efficacy by SHP2 and RTK Inhibitors in KRAS-Mutant Cancers

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• KRAS is a key oncogene mutated in approximately one-third of human cancers.
• Direct inhibition of KRAS remains a significant therapeutic challenge, with recent progress in targeting the G12C variant.
• SHP2 (SH2 domain-containing phosphatase 2) is a protein tyrosine phosphatase implicated in various cellular signaling pathways.

Purpose of the Study:

• To investigate the therapeutic potential of selective SHP2 inhibition in KRAS-mutant cancers.
• To elucidate the mechanisms underlying the anti-proliferative effects of SHP2 inhibition in KRAS-mutant cancer models.
• To explore the relationship between receptor tyrosine kinase (RTK) activity, SHP2 activation, and cancer cell dependency.

Main Methods:

• Utilized an allosteric SHP2 inhibitor (SHP099) in KRAS-mutant cancer cell lines.
• Assessed cellular proliferation and pathway modulation in 2D monolayer and 3D multicellular spheroid cultures.
• Evaluated *in vivo* efficacy using cell line xenografts and primary human tumor models in mice.
• Investigated the mitogen-activated protein kinase (MAPK) pathway and receptor tyrosine kinase (RTK) signaling.

Main Results:

• Selective SHP2 inhibition impaired KRAS-mutant cancer cell proliferation *in vitro* and *in vivo*.
• Sensitivity to SHP099 was evident in 3D spheroids and *in vivo* models, but not in 2D monolayers.
• MAPK pathway modulation (p-ERK, DUSP6) was observed, suggesting pathway-dependent and potentially independent mechanisms.
• SHP099 efficacy was cancer cell-intrinsic and could be recapitulated by RTK inhibitors, indicating RTK-driven SHP2 activation.

Conclusions:

• KRAS-mutant cancers exhibit dependency on upstream RTK and SHP2 signaling.
• SHP2 inhibitors represent a promising therapeutic framework for treating KRAS-mutant cancers.
• The study highlights the importance of 3D culture models for revealing drug sensitivity in cancer research.