Activity and Mechanism of Acquired Resistance to Tarloxotinib in Mutant Lung Cancer: an Study

Overview

Journal Transl Lung Cancer Res

Date 2021 Sep 29

PMID 34584864

Citations 7

Authors

Takamasa Koga

Kenichi Suda

Masaya Nishino

Toshio Fujino

Shuta Ohara

Akira Hamada

Junichi Soh

Vijaya Tirunagaru

Avanish Vellanki

Robert C Doebele

Tetsuya Mitsudomi

Affiliations

Soon will be listed here.

Abstract

Background: () activating mutations are present in 2-3% of lung adenocarcinomas; however, no targeted therapy is approved for -altered lung cancers. A novel pan-HER inhibitor, tarloxotinib, is designed to release the active form (tarloxotinib-E) under hypoxic conditions in tumor tissues after being administered as a prodrug. Following the evaluation of the activity of tarloxotinib-E in -mutant cells, we explored the mechanisms of resistance to tarloxotinib-E in these cells.

Methods: Growth inhibitory assays were performed with tarloxotinib-E and its prodrug using Ba/F3 cells expressing one of six mutations or wild-type (WT) , in addition to H1781 cells with exon 20 insertions. Resistant clones were established from N-ethyl-N-nitrosourea (ENU)-treated -mutant Ba/F3 cells and H1781 cells by chronic exposure to tarloxotinib-E.

Results: Tarloxotinib-E showed potent activity against -mutant Ba/F3 cells and H1781 cells. Furthermore, the half maximal inhibitory concentration (IC) of tarloxotinib (inactive form) for WT was 180 times higher than that of tarloxotinib-E, indicating a wide therapeutic window of tarloxotinib. We established 30 resistant clones with secondary mutations of by ENU mutagenesis, all of which harbored C805S in exon 20. In the analysis of H1781 cells that acquired resistance to tarloxotinib-E, we found that increased expression was the molecular mechanism of tarloxotinib-E resistance.

Conclusions: Tarloxotinib-E exhibited potent activity against cell line models with mutations. We identified a secondary C805S mutation and overexpression as the mechanisms of acquired resistance to tarloxotinib-E.

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