Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancer

Author:

Katayama Yuki,Yamada TadaakiORCID,Tanimura Keiko,Tokuda Shinsaku,Morimoto Kenji,Hirai Soichi,Matsui Yohei,Nakamura Ryota,Ishida Masaki,Kawachi Hayato,Yoneda Kazue,Hosoya Kazutaka,Tsuji Takahiro,Ozasa Hiroaki,Yoshimura AkihiroORCID,Iwasaku Masahiro,Kim Young Hak,Horinaka Mano,Sakai Toshiyuki,Utsumi Takahiro,Shiotsu Shinsuke,Takeda TakayukiORCID,Katayama RyoheiORCID,Takayama KoichiORCID

Abstract

AbstractAnaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underlying adaptive resistance to lorlatinib and therapeutic strategies required to overcome them. We found that epidermal growth factor receptor (EGFR) signaling was involved in the adaptive resistance to lorlatinib in ALK-rearranged NSCLC, activation of which was induced by heparin-binding EGF-like growth factor production via c-Jun activation. EGFR inhibition halted ALK-rearranged lung cancer cell proliferation by enhancing ALK inhibition-induced apoptosis via suppression of Bcl-xL. Xenograft models showed that the combination of EGFR inhibitor and lorlatinib considerably suppressed tumor regrowth following cessation of these treatments. This study provides new insights regarding tumor evolution due to EGFR signaling after lorlatinib treatment and the development of combined therapeutic strategies for ALK-rearranged lung cancer.

Funder

Pfizer Inc. | Pfizer Japan

MEXT | Japan Society for the Promotion of Science

Medical Research Continuous Grants of Takeda Science Foundation Research Grant of the Princess Takamatsu Cancer Research Fund

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology

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