Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance

Abstract

Background: Non-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond to first-generation EGFR inhibitors; however, the efficacy of these drugs is limited by acquired resistance driven by the EGFR T790M mutation. The discovery of third-generation EGFR inhibitors overcoming EGFR T790M and their new resistance mechanisms have attracted much attention. Methods: We examined the antitumor activities and potential resistance mechanism of a novel EGFR thirdgeneration inhibitor in vitro and in vivo using ELISA, SRB assay, immunoblotting, flow cytometric analysis, kinase array, qRT-PCR and tumor xenograft models. The clinical effect on a patient was evaluated by computed tomography scan. Results: We identified compound ASK120067 as a novel inhibitor of EGFR T790M , with selectivity over EGFR WT. ASK120067 exhibited potent anti-proliferation activity in tumor cells harboring EGFR T790M (NCI-H1975) and sensitizing mutations (PC-9 and HCC827) while showed moderate or weak inhibition in cells expressing EGFR WT. Oral administration of ASK120067 induced tumor regression in NSCLC xenograft models and in a PDX model harboring EGFR T790M. The treatment of one patient with advanced EGFR T790M-positive NSCLC was described as proof of principle. Moreover, we found that hyperphosphorylation of Ack1 and the subsequent activation of antiapoptotic signaling via the AKT pathway contributed to ASK120067 resistance. Concomitant targeting of EGFR and Ack1 effectively overrode the acquired resistance of ASK120067 both in vitro and in vivo. Conclusions: Our results idenfity ASK120067 as a promising third-generation EGFR inhibitor and reveal for the first time that Ack1 activation as a novel resistance mechanism to EGFR inhibitors that guide to potential combination strategy.

Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC

“…Sources of the structures: almonertinib, 12 larzertinib, 18 alflutinib, 26 rezivertinib (https://www.medkoo.com/products/36827), ASK120067. 37 TKI, tyrosine kinase inhibitor. (ALT) elevation (11.4%), leukopenia (11.2%), and pruritus (10.7%).…”

“…The GI 50 against L858R/T790M is 12 nM (NCI-H1975), EGFR del19 6 nM (PC-9), and EGFR L858R 2nM (HCC827). 37 Both phase 1, phase 2 and randomized phase 3 trials have been registered and are ongoing (Fig. 1 and Table 1).…”

Epitope Mapping of an Antihuman EGFR Monoclonal Antibody (EMab-134) Using the REMAP Method

“…Although EGFR-targeting therapies, such as EGFR tyrosine kinase inhibitors and anti-EGFR monoclonal antibodies (mAbs), show some antitumor efficacy in clinical trials, tumors can evolve with EGFR-resistant mutations, thereby causing failure of these therapies. (9)(10)(11)(12)(13)(14) Thus, EGFR-targeting drugs are needed to overcome these mutations.…”

Significant Gene Biomarker Tyrosine Kinase Non-receptor 2 Mediated Cell Proliferation and Invasion in Colon Cancer

“…In non-small cell lung cancer, TNK2 might affects the development of tumors by influencing the tumor immune microenvironment (Zhu et al, 2020 ). Moreover, TNK2 activation as a novel mechanism of EGFR inhibitor resistance is revealed for the guiding potential combined strategies (Zhang et al, 2020 ). In castration-resistant prostate cancer, TNK2 drives the malignant state via a feed-forward ACK1/pY88-H4/WDR5/MLL2/AR epigenetic circuit (Mahajan et al, 2017 ).…”