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ERK inhibitor ASN007 effectively overcomes acquired resistance to EGFR inhibitor in non-small cell lung cancer

The 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.

 

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The passage you provided highlights the issue of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR mutations. It suggests that increased activation of the ERK signaling pathway is associated with acquired resistance to EGFR TKIs. To address this problem, the researchers investigated the efficacy of ASN007, a potent selective ERK1/2 inhibitor, in EGFR TKI-resistant cells and xenograft models.

The study found that ASN007 treatment inhibited tumor cell growth and disrupted the cell cycle in EGFR TKI-resistant cells. Furthermore, combining ASN007 with EGFR TKIs led to decreased survival of resistant cells, enhanced induction of apoptosis (programmed cell death), and effectively suppressed the growth of erlotinib-resistant xenografts (tumor models).

These findings suggest that targeting the ERK signaling pathway, specifically with ASN007, could potentially overcome acquired resistance to EGFR TKIs in EGFR-mutated NSCLC patients. The study provides a preclinical rationale for testing the combination of ASN007 and EGFR TKIs in clinical trials for these patients.

By combining an EGFR TKI with an ERK inhibitor like ASN007, researchers hope to improve the long-term efficacy of EGFR TKIs and overcome acquired resistance, ultimately enhancing treatment outcomes for EGFR-mutated NSCLC patients. However, it's important to note that further studies, including clinical trials, are needed to confirm the safety and efficacy of this combination therapy in human patients.

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S9975 ASN007 ASN007(ERAS 007, ERK-IN-3) is a potent and orally active inhibitor of ERK. ERK-IN-3 inhibits ERK1/2 with 2 nM IC50 values. ERK-IN-3 can be used for the research of cancers driven by RAS mutations.

Related Targets

ERK