Tackling Drug Resistance in EGFR Exon 20 Insertion Mutant Lung Cancer

Abstract

Insertion mutations in exon 20 (Ex20ins) of the epidermal growth factor receptor ( EGFR ) gene are the largest class of EGFR mutations in non-small cell lung cancer (NSCLC) for which there are currently no approved targeted therapies. NSCLC patients with these mutations do not respond to clinically approved EGFR tyrosine kinase inhibitors (TKIs) and have poor outcomes. A number of early phase clinical trials are currently underway to evaluate the efficacy of a new generation of TKIs that are capable of binding to and blocking Ex20ins. Although these agents have shown some clinical activity, patient responses have been restricted by dose-limiting toxicity or rapid acquisition of resistance after a short response. Here we review the current understanding of the mechanisms of resistance to these compounds, which include on-target EGFR secondary mutations, compensatory bypass pathway activation and acquisition of an EMT phenotype. Taking lessons from conventional EGFR inhibitor therapy in NSCLC, we also consider other potential sources of resistance including the presence of drug-tolerant persister cells. We will discuss therapeutic strategies which have the potential to overcome different forms of drug resistance. We conclude by evaluating recent technological developments in drug discovery such as PROTACs as a means to better tackle TKI resistance in NSCLC harbouring Ex20ins mutations.

GZ17-6.02 and Pemetrexed Interact to Kill Osimertinib-Resistant NSCLC Cells That Express Mutant ERBB1 Proteins

“…A subset of NSCLC patients present with tumors whose biology is driven by expression of mutated active forms of ERBB1. Some of the mutant ERBB1 proteins are point mutation mutants and others are deletion mutants ( 10 , 11 ). Multiple ERBB1 inhibitors are approved to treat this form of the disease including erlotinib, afatinib, and recently osimertinib.…”

“…The treatment of NSCLC over the past 20 years has been revolutionized, first by the development of the pemetrexed carboplatin drug combination and then subsequently by checkpoint inhibitory immunotherapy (10)(11)(12)(13)(14). For NSCLC tumors expressing mutant RAS proteins or without a clear oncogenic driver, the combination of pemetrexed, carboplatin, and an anti-PD1 antibody, e.g., pembrolizumab, is a standard of care therapeutic approach.…”

EGFR Exon 20 Insertion Mutations in Sinonasal Squamous Cell Carcinoma

“…Taking lessons from EGFR inhibitor therapy in NSCLC, several mechanisms of resistance can be predicted in the context of SNSCC. The most common mechanisms include on-target EGFR secondary mutations, compensatory bypass pathway activation, the acquisition of an epithelial to mesenchymal transition (EMT) phenotype and the presence of drug-tolerant persister (DTP) cells in the heterogeneous tumour population [ 92 ]. Specifically, clinical mechanisms of resistance have been reported for some of the Ex20ins inhibitors mentioned before [ 93 ].…”

“…These EMT-driven, erlotinib-resistant cells also showed resistance to poziotinib, indicating that poziotinib may be susceptible to similar mechanisms of acquired resistance as other EGFR TKIs that target classical EGFR mutations [ 52 ]. Finally, it is now well established that the subpopulation of DTP cells that remain viable in the presence of anti-cancer treatments despite not harbouring classic genetic mutations can contribute to acquired resistance to first- and third-generation EGFR TKIs in NSCLC cell line models [ 92 , 105 , 106 , 107 ]. This knowledge from classical EGFR mutations in lung cancer is important as it allows us to anticipate the potential routes of drug resistance to EGFR Ex20ins inhibitors in other clinical settings, such as in SNSCC.…”

Taxus wallichiana var. chinensis (Pilg.) Florin Aqueous Extract Suppresses the Proliferation and Metastasis in Lung Carcinoma via JAK/STAT3 Signaling Pathway

“…According to the American Cancer Society, there were 228,820 new cases and 135,720 deaths of LC in 2020, and LC ranked the first among malignancies ( Miller et al, 2020 ). Furthermore, invasion and metastasis along with unlimited reproduction of LC cells induce poor response or even resistance to routine clinical strategies, further decreasing the survival ( Abadi et al, 2021 ; Pacini et al, 2021 ). Therefore, searching for effective therapeutic strategies and targets is urgent and essential.…”