ERK inhibitor ASN007 effectively overcomes acquired resistance to EGFR inhibitor in non\u2010small cell lung cancer

Bo Mi Ku,Jae Yeong Heo,Jong-Mu Sun,Jin Seok Ahn,Myung-Ju Ahn,Se-Hoon Lee,Keunchil Park,Jinchul Kim

doi:10.1007/s10637-021-01121-6

Bo Mi Ku, Jae Yeong Heo + Show 6 more

Open Access

https://doi.org/10.1007/s10637-021-01121-6

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Abstract

SummaryThe emergence of acquired resistance limits the long-term efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs). Thus, development of effective strategies to overcome resistance to EGFR TKI is urgently needed. Multiple mechanisms to reactivate ERK signaling have been successfully demonstrated in acquired resistance models. We found that in EGFR mutant non-small cell lung cancer (NSCLC) patients, acquired resistance to EGFR TKIs was accompanied by increased activation of ERK. Increased ERK activation was also found in in vitro models of acquired EGFR TKI resistance. ASN007 is a potent selective ERK1/2 inhibitor with promising antitumor activity in cancers with BRAF and RAS mutations. ASN007 treatment impeded tumor cell growth and the cell cycle in EGFR TKI-resistant cells. In addition, combination treatment with ASN007 and EGFR TKIs significantly decreased the survival of resistant cells, enhanced induction of apoptosis, and effectively inhibited the growth of erlotinib-resistant xenografts, providing the preclinical rationale for testing combinations of ASN007 and EGFR TKIs in EGFR-mutated NSCLC patients. This study emphasizes the importance of targeting ERK signaling in maintaining the long-term benefits of EGFR TKIs by overcoming acquired resistance.

Highlights

EGFR tyrosine kinase inhibitors (EGFR TKIs) significantly improve clinical outcomes in patients with nonsmall cell lung cancer (NSCLC) harboring EGFR mutations, such as exon 19 deletion and the L858R mutation, almost all mutant EGFR-positive NSCLC patients acquire resistance to EGFR TKIs after approximately 1–2 years [1]
Aberrant activation of ERK signaling was found in erlotinib, gefitinib, osimertinib, and WZ4002-resistant NSCLC cells [2, 5,6,7,8,9,10,11,12]
Acquired resistance to EGFR TKI is related to increased ERK activation in NSCLC tumor tissue

Summary

Introduction

EGFR tyrosine kinase inhibitors (EGFR TKIs) significantly improve clinical outcomes in patients with nonsmall cell lung cancer (NSCLC) harboring EGFR mutations, such as exon 19 deletion and the L858R mutation, almost all mutant EGFR-positive NSCLC patients acquire resistance to EGFR TKIs after approximately 1–2 years [1]. Previous studies have demonstrated that sustained ERK activation is involved in resistance to EGFR TKIs. targeting MEK-ERK signaling through either an MEK or ERK inhibitor can overcome acquired resistance to EGFR TKIs. Aberrant activation of ERK signaling was found in erlotinib-, gefitinib-, osimertinib-, and WZ4002-resistant NSCLC cells [2, 5,6,7,8,9,10,11,12]. In erlotinib- and gefitinib-resistant cells, the combination of EGFR TKI with an MEK inhibitor effectively inhibited tumor growth and impeded the development of resistance [8, 9]. MEK inhibition using trametinib combined with WZ4002 was shown to delay the emergence of acquired resistance to WZ4002 in NSCLC [4]

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