TY - JOUR
T1 - SHOC2 is a critical modulator of sensitivity to EGFR–TKIs in non–small cell lung cancer cells
AU - Terai, Hideki
AU - Hamamoto, Junko
AU - Emoto, Katsura
AU - Masuda, Takeshi
AU - Manabe, Tadashi
AU - Kuronuma, Satoshi
AU - Kobayashi, Keigo
AU - Masuzawa, Keita
AU - Ikemura, Shinnosuke
AU - Nakayama, Sohei
AU - Kawada, Ichiro
AU - Suzuki, Yusuke
AU - Takeuchi, Osamu
AU - Suzuki, Yukio
AU - Ohtsuki, Sumio
AU - Yasuda, Hiroyuki
AU - Soejima, Kenzo
AU - Fukunaga, Koichi
N1 - Funding Information:
K. Soejima reports grants from AstraZeneca, Nippon Boehringer Ingelheim, and Taiho Pharmaceutical, as well as personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb Japan, MSD Oncology, Lily Japan, Taiho Pharmaceutical, Nippon Kayaku, and Novartis Pharma outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
This work was supported in part by the Japan Society for the Promotion of Science (grant #18K08184; to H. Terai) and (grant #17K09667; to H. Yasuda). This work was also supported in part by grants awarded by the Takeda Science Foundation (to H. Yasuda and H. Terai). We thank Dr. David Barbie (Dana Farber Cancer Institute, Boston, MA) and Peter Hammerman (Novartis Institutes of Biomedical Research, Cambridge, MA) for their advice. The authors thank Chinatsu Yonekawa, Mikiko Shibuya, Miho Takeoka, Yui Kakishima, and Nodoka Adegawa for their technical assistance. We would like to thank Editage (www.editage.com) for English language editing.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - EGFR mutation-positive patients with non–small cell lung cancer (NSCLC) respond well to treatment with EGFR–tyrosine kinase inhibitors (EGFR–TKI); 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. On the basis of 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. In addition, we confirmed that SHOC2 expression levels were important for the sensitivity to EGFR–TKIs in vivo. Furthermore, IHC showed the accumulation of cancer cells that express high levels of SHOC2 in lung cancer tissues obtained from patients with NSCLC who experienced acquired resistance to EGFR–TKIs. These data indicate that SHOC2 may be a therapeutic target for patients with NSCLC or a biomarker to predict sensitivity to EGFR–TKI therapy in EGFR mutation-positive patients with NSCLC. Our findings may help improve treatment strategies for patients with NSCLC 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.
AB - EGFR mutation-positive patients with non–small cell lung cancer (NSCLC) respond well to treatment with EGFR–tyrosine kinase inhibitors (EGFR–TKI); 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. On the basis of 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. In addition, we confirmed that SHOC2 expression levels were important for the sensitivity to EGFR–TKIs in vivo. Furthermore, IHC showed the accumulation of cancer cells that express high levels of SHOC2 in lung cancer tissues obtained from patients with NSCLC who experienced acquired resistance to EGFR–TKIs. These data indicate that SHOC2 may be a therapeutic target for patients with NSCLC or a biomarker to predict sensitivity to EGFR–TKI therapy in EGFR mutation-positive patients with NSCLC. Our findings may help improve treatment strategies for patients with NSCLC 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.
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U2 - 10.1158/1541-7786.MCR-20-0664
DO - 10.1158/1541-7786.MCR-20-0664
M3 - Article
C2 - 33106373
AN - SCOPUS:85100412001
VL - 19
SP - 317
EP - 328
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
SN - 1541-7786
IS - 2
ER -