TY - JOUR
T1 - Activation of AXL as a preclinical acquired resistance mechanism against osimertinib treatment in EGFR-mutant non-small cell lung cancer cells
AU - Namba, Kei
AU - Shien, Kazuhiko
AU - Takahashi, Yuta
AU - Torigoe, Hidejiro
AU - Sato, Hiroki
AU - Yoshioka, Takahiro
AU - Takeda, Tatsuaki
AU - Kurihara, Eisuke
AU - Ogoshi, Yusuke
AU - Yamamoto, Hiromasa
AU - Sou, Junichi
AU - Tomida, Shuta
AU - Toyooka, Shinichi
N1 - Funding Information:
The authors thank Dr. Takehiro Matsubara, Ms. Yuko Hanafusa (Okayama University Hospital Biobank, Okayama University Hospital, Okayama, Japan), and Ms. Fumiko Isobe (Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan) for their technical support. This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPSKAKENHI grant nos. 17K16608, to K. Shien; 16H05431, to S. Toyooka).
Funding Information:
The authors thank Dr. Takehiro Matsubara, Ms. Yuko Hanafusa (Okayama University Hospital Biobank, Okayama University Hospital, Okayama, Japan), and Ms. Fumiko Isobe (Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan) for their technical support. This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS KAKENHI grant nos. 17K16608, to K. Shien; 16H05431, to S. Toyooka).
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/2
Y1 - 2019/2
N2 - Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib- resistant cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multigene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib. Implications: Upregulation of AXL is one of the mechanisms of acquired resistance to osimertinib, and combination of osimertinib and cabozantinib might be a key treatment for overcoming osimertinib resistance.
AB - Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib- resistant cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multigene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib. Implications: Upregulation of AXL is one of the mechanisms of acquired resistance to osimertinib, and combination of osimertinib and cabozantinib might be a key treatment for overcoming osimertinib resistance.
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U2 - 10.1158/1541-7786.MCR-18-0628
DO - 10.1158/1541-7786.MCR-18-0628
M3 - Article
C2 - 30463991
AN - SCOPUS:85060954764
VL - 17
SP - 499
EP - 507
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
SN - 1541-7786
IS - 2
ER -