LTK Mutations Responsible for Resistance to Lorlatinib in Non-small Cell Lung Cancer Harboring CLIP1-LTK Fusion

Overview

Journal Commun Biol

Specialty Biology

Date 2024 Apr 4

PMID 38575808

Authors

Shunta Mori

Hiroki Izumi

Mitsugu Araki

Jie Liu

Yu Tanaka

Yosuke Kagawa

Yukari Sagae

Biao Ma

Yuta Isaka

Yoko Sasakura

Shogo Kumagai

Yuta Sakae

Kosuke Tanaka

Yuji Shibata

Hibiki Udagawa

Shingo Matsumoto

Kiyotaka Yoh

Yasushi Okuno

Koichi Goto

Susumu S Kobayashi

Affiliations

Soon will be listed here.

Abstract

The CLIP1-LTK fusion was recently discovered as a novel oncogenic driver in non-small cell lung cancer (NSCLC). Lorlatinib, a third-generation ALK inhibitor, exhibited a dramatic clinical response in a NSCLC patient harboring CLIP1-LTK fusion. However, it is expected that acquired resistance will inevitably develop, particularly by LTK mutations, as observed in NSCLC induced by oncogenic tyrosine kinases treated with corresponding tyrosine kinase inhibitors (TKIs). In this study, we evaluate eight LTK mutations corresponding to ALK mutations that lead to on-target resistance to lorlatinib. All LTK mutations show resistance to lorlatinib with the L650F mutation being the highest. In vitro and in vivo analyses demonstrate that gilteritinib can overcome the L650F-mediated resistance to lorlatinib. In silico analysis suggests that introduction of the L650F mutation may attenuate lorlatinib-LTK binding. Our study provides preclinical evaluations of potential on-target resistance mutations to lorlatinib, and a novel strategy to overcome the resistance.

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