Mol Cancer Res. 2020 Oct 26:molcanres.0664.2020. doi: 10.1158/1541-7786.MCR-20-0664. Online ahead of print.
Epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients respond well to treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs); however, treatment with EGFR-TKIs is not curative, owing to the presence of residual cancer cells with intrinsic or acquired resistance to this class of drugs. Additional treatment targets that may enhance the efficacy of EGFR-TKIs remain elusive. Using a CRISPR/Cas9-based screen, we identified the leucine-rich repeat
scaffold protein SHOC2 as a key modulator of sensitivity to EGFR-TKI treatment. Based on in vitro assays, we demonstrated that SHOC2 expression levels strongly correlate with the sensitivity to EGFR-TKIs and that SHOC2 affects the sensitivity to EGFR-TKIs in NSCLC cells via SHOC2/MRAS/PP1c and SHOC2/SCRIB signaling. The potential SHOC2 inhibitor celastrol phenocopied SHOC2 depletion. Additionally, we confirmed that SHOC2 expression levels were important for the sensitivity to EGFR-TKIs in vivo. Furthermore, immunohistochemistry showed the accumulation of cancer cells that express high levels of SHOC2 in lung cancer tissues obtained from NSCLC patients who experienced acquired resistance to EGFR-TKIs. These data indicate that SHOC2 may be a therapeutic target for NSCLC patients or a biomarker to predict sensitivity to EGFR-TKI therapy in EGFR mutation-positive NSCLC patients. Our findings may help improve treatment strategies for NSCLC patients harboring EGFR mutations. Implications: This study showed that SHOC2 works as a modulator of sensitivity to EGFR-TKIs and the expression levels of SHOC2 can be used as a biomarker for sensitivity to EGFR-TKIs.