Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of ALK-Rearranged Lung Cancer

Introduction: Leptomeningeal carcinomatosis (LMC) occurs frequently in anaplastic lymphoma kinase (ALK)–rearranged NSCLC and develops acquired resistance to ALK tyrosine kinase inhibitors (ALK TKIs). This study aimed to clarify the resistance mechanism to alectinib, a second-generation ALK TKI, in LMC and test a novel therapeutic strategy. Conclusions: These findings indicate the potential of novel therapies targeting both ALK and EGFR for the treatment of ALK TKI–resistant LMC in ALK-rearranged NSCLC. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.01.001

Authors: Sachiko Arai, Shinji Takeuchi, Koji Fukuda, Hirokazu Taniguchi, Akihiro Nishiyama, Azusa Tanimoto, Miyako Satouchi, Kaname Yamashita, Koshiro Ohtsubo, Shigeki Nanjo, Toru Kumagai, Ryohei Katayama, Makoto Nishio, Mei-mei Zheng, Yi-Long Wu, Hiroshi Nishihara, Takushi Yamamoto M.Eng, Mitsutoshi Nakada, Seiji Yano

Pre-ClinicalKirk SmithJanuary 20, 2020Leptomeningeal metastasis, EML4-ALK, Alectinib resistance, Osimertinib

Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of EML4-ALK Lung Cancer

Background: Central nervous system (CNS) metastasis, such as brain metastasis and leptomeningeal carcinomatosis (LMC), occurs in 20–40% of all patients with cancer. Anaplastic lymphoma kinase (ALK) is a clinically validated drug target and ALK rearrangements are found in approximately 3-5% of non-small cell lung cancer (NSCLC). ALK tyrosine kinase inhibitor (TKI) shows dramatic clinical efficacy in ALK-rearranged NSCLC patients, and the second-generation ALK-TKI alectinib is effective against CNS metastasis of ALK-rearranged NSCLC. However, the patients with ALK-rearrangement acquire resistance to alectinib over time and develop recurrent LMC metastasis. This study aimed to clarify the mechanism of resistance to alectinib in LMC and seek a novel therapeutic strategy. Conclusion: We demonstrated that EML4-ALK lung cancer cells acquired moderate resistance to alectinib in the leptomeningeal space due to amphiregulin-triggered EGFR activation. Moreover, combined use of alectinib and EGFR..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1841

Authors: S. Arai, S. Takeuchi, K. Fukuda, A. Nishiyama, A. Tanimoto, H. Taniguchi, M. Satouchi, S. Nanjo, R. Katayama, M. Nishio, M. Zheng, Y. Wu, S. Yano

Conference PaperKirk SmithOctober 1, 2019Leptomeningeal carcinomatosis, alectinib resistance, Osimertinib