학술논문
Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancer
Document Type
article
Author
Yuki Katayama; Tadaaki Yamada; Keiko Tanimura; Shinsaku Tokuda; Kenji Morimoto; Soichi Hirai; Yohei Matsui; Ryota Nakamura; Masaki Ishida; Hayato Kawachi; Kazue Yoneda; Kazutaka Hosoya; Takahiro Tsuji; Hiroaki Ozasa; Akihiro Yoshimura; Masahiro Iwasaku; Young Hak Kim; Mano Horinaka; Toshiyuki Sakai; Takahiro Utsumi; Shinsuke Shiotsu; Takayuki Takeda; Ryohei Katayama; Koichi Takayama
Source
npj Precision Oncology, Vol 7, Iss 1, Pp 1-13 (2023)
Subject
Language
English
ISSN
2397-768X
Abstract
Abstract Anaplastic 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.