Abstract
(1) Background: Mutations in epidermal growth factor receptor (EGFR) proteins account for many non-small cell lung cancers (NSCLCs), and EGFR tyrosine kinase inhibitors (TKIs) are being used as targeted therapeutics. However, resistance to TKIs continues to increase owing to additional mutations in more than half of the patients receiving EGFR TKI therapy. In addition to targeting new mutations with next-generation therapeutics, it is necessary to find an alternative target to overcome the challenges associated with resistance. (2) Methods: To identify potential alternative targets in patients with NSCLC undergoing targeted therapy, putative targets were identified by transcriptome profiling and validated for their biological and therapeutic effects in vitro and in vivo. (3) Results: ELF3 was found to be differentially expressed in NSCLC, and ELF3 knockdown significantly increased cell death in K-Ras mutant as well as in EGFR L858R/T790M mutation harboring lung cancer cells. We also found that auranofin, an inhibitor of protein kinase C iota (PKCί), a protein upstream of ELF3, effectively induced cell death. (4) Conclusions: Our study suggests that blocking ELF3 is an effective way to induce cell death in NSCLC with K-Ras and EGFR T790M/L858R mutations and thus advocates the use of auranofin as an effective alternative drug to overcome EGFR TKI resistance.
Highlights
Lung cancer was the second most commonly diagnosed cancer (11.4%) and the leading cause of cancer-related deaths (18.0%) worldwide in 2020 [1]
(4) Conclusions: Our study suggests that blocking ELF3 is an effective way to induce cell death in non-small cell lung cancers (NSCLCs) with K-Ras and epidermal growth factor receptor (EGFR) T790M/L858R mutations and advocates the use of auranofin as an effective alternative drug to overcome EGFR tyrosine kinase inhibitors (TKIs) resistance
Except for one case of stable disease (SD), most patient-derived cells (PDCs) were from patients with progressive disease (PD) or partial response (PR) to therapies
Summary
Lung cancer was the second most commonly diagnosed cancer (11.4%) and the leading cause of cancer-related deaths (18.0%) worldwide in 2020 [1]. To target EGFR mutations, first-generation EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have been developed and applied as targeted therapies. NSCLC patients treated with first-generation EGFR TKIs develop resistance in 10–19 months by acquisition of a second point mutation in the kinase domain of EGFR (T790M). The T790M mutation accounts for approximately 50–60% of acquired resistance and abolishes the effect of first-generation TKI by distorting the ATP-binding pocket to block the binding of the EGFR TKI. To overcome acquired mutation-based resistance, second-generation EGFR TKIs (e.g., afatinib) and third generation TKIs (e.g., osimertinib) have been developed. Additional mutations (e.g., EGFR C797S) rendered the newly developed drugs ineffective [3]. It is necessary to develop new strategies to overcome the challenges associated with targeted drugs for EGFR mutants that are rendered ineffective due to the occurrence of unexpected mutations
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