SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• The ERK-MAPK pathway is frequently upregulated in human cancers, but targeted inhibition faces challenges like drug resistance and toxicity.
• The MRAS-SHOC2-PP1 complex, or SHOC2 phosphatase, is crucial for RAF-ERK pathway activation by dephosphorylating RAF kinases.
• Developing effective therapies against this pathway remains a significant clinical need.

Purpose of the Study:

• To investigate the therapeutic potential of targeting SHOC2 phosphatase in KRAS-mutant non-small cell lung cancer (NSCLC).
• To evaluate the efficacy of SHOC2 inhibition as a monotherapy and in combination with MEK inhibitors.
• To elucidate the underlying mechanisms by which SHOC2 deletion impacts tumor growth and drug sensitivity.

Main Methods:

• Genetic inhibition of SHOC2 in KRAS-mutant NSCLC cell lines and autochthonous murine lung cancer models.
• Assessment of tumor growth suppression and tolerability of systemic SHOC2 ablation in adult mice.
• Analysis of SHOC2 deletion's effect on MEK inhibitor (MEKi) sensitivity in KRAS- and EGFR-mutant NSCLC cells.
• Mechanistic studies involving RAF dimerization, ERK pathway suppression, and BIM-dependent apoptosis.

Main Results:

• Genetic SHOC2 inhibition suppressed tumorigenic growth in a subset of KRAS-mutant NSCLC cell lines.
• SHOC2 inhibition prominently inhibited tumor development in KRAS-driven murine lung cancer models.
• Systemic SHOC2 ablation in adult mice was relatively well tolerated.
• SHOC2 deletion selectively sensitized KRAS- and EGFR-mutant NSCLC cells to MEK inhibitors.
• SHOC2 deletion prevented MEKi-induced RAF dimerization, leading to enhanced ERK pathway suppression and BIM-dependent apoptosis.

Conclusions:

• SHOC2 phosphatase is a viable therapeutic target for KRAS-driven NSCLC.
• Targeting SHOC2 offers a potential monotherapy strategy and can enhance the efficacy of MEK inhibitors.
• SHOC2 inhibition presents a promising approach to overcome drug resistance and improve the therapeutic index of MEK inhibitors in NSCLC.