American Association for Cancer Research
10780432ccr180304-sup-196126_2_supp_4918798_pcg4km.pdf (170.49 kB)

Table S3 from Increased Synthesis of MCL-1 Protein Underlies Initial Survival of EGFR-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target

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journal contribution
posted on 2023-03-31, 20:50 authored by Kyung-A Song, Yasuyuki Hosono, Crystal Turner, Sheeba Jacob, Timothy L. Lochmann, Yoshiko Murakami, Neha U. Patel, Jungoh Ham, Bin Hu, Krista M. Powell, Colin M. Coon, Brad E. Windle, Yuko Oya, Jennifer E. Koblinski, Hisashi Harada, Joel D. Leverson, Andrew J. Souers, Aaron N. Hata, Sosipatros Boikos, Yasushi Yatabe, Hiromichi Ebi, Anthony C. Faber

Sup. Table 3. Fold change of FBX7 from RNA-seq analysis.




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Japan Society for the Promotion of Science

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Purpose: EGFR inhibitors (EGFRi) are effective against EGFR-mutant lung cancers. The efficacy of these drugs, however, is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, T790M. We recently demonstrated that T790M can arise de novo during treatment; it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells [referred to as drug-tolerant cells (DTC)] prior to acquiring secondary mutations like T790M.Experimental Design: We have developed DTCs to EGFRi in EGFR-mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink EGFR-mutant lung cancer tumors in vivo.Results: We demonstrate surviving EGFR-mutant lung cancer cells upregulate the antiapoptotic protein MCL-1 in response to short-term EGFRi treatment. Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors. Moreover, MCL-1 is a key molecule governing the emergence of early EGFR-mutant DTCs to EGFRi, and we demonstrate it can be effectively cotargeted with clinically emerging MCL-1 inhibitors both in vitro and in vivo.Conclusions: Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy. Clin Cancer Res; 24(22); 5658–72. ©2018 AACR.

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