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

Content Provider	Europe PMC
Author	Katayama, Yuki Yamada, Tadaaki 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, Akihiro Iwasaku, Masahiro Kim, Young Hak Horinaka, Mano Sakai, Toshiyuki Utsumi, Takahiro Shiotsu, Shinsuke Takeda, Takayuki Katayama, Ryohei Takayama, Koichi
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.
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Journal	NPJ Precision Oncology [NPJ Precis Oncol]
Volume Number	7
DOI	10.1038/s41698-023-00350-7
PubMed Central reference number	PMC9879975
Issue Number	1
PubMed reference number	36702855
e-ISSN	2397768X
Language	English
Publisher	Nature Publishing Group UK
Publisher Date	2023-01-26
Publisher Place	London
Access Restriction	Open
Rights License	Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2023
Subject Keyword	Non-small-cell lung cancer Cancer therapeutic resistance Targeted therapies
Content Type	Text
Resource Type	Article
Subject	Oncology Cancer Research