UMMS Affiliation

RNA Therapeutics Institute

Publication Date

2019-08-20

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Cancer Biology | Cells | Neoplasms | Oncology

Abstract

Drug resistance and tumor heterogeneity are formidable challenges in cancer medicine, which is particularly relevant for KRAS-mutant cancers, the epitome of malignant tumors recalcitrant to targeted therapy efforts and first-line chemotherapy. In this study, we delineate that KRAS-mutant lung cancer cells resistant to pemetrexed (MTA) and anti-MEK drug trametinib acquire an exquisite dependency on endoplasmic reticulum (ER) stress signaling, rendering resistant cancer cells selectively susceptible to blockage of HSP90, the receptor tyrosine kinase AXL, the eukaryotic translation initiation factor 4E (eIF4E), and the unfolded protein response (UPR). Mechanistically, acquisition of drug resistance enables KRAS-mutant lung cancer cells to bypass canonical KRAS effectors but entail hyperactive AXL/eIF4E, increased protein turnover in the ER, and adaptive activation of an ER stress-relief UPR survival pathway whose integrity is maintained by HSP90. Notably, the unique dependency and sensitivity induced by drug resistance are applicable to KRAS-mutant lung cancer cells undergoing de novo intratumor heterogeneity. In line with these findings, HSP90 inhibitors synergistically enhance antitumor effects of MTA and trametinib, validating a rational combination strategy to treat KRAS-mutant lung cancer. Collectively, these results uncover collateral vulnerabilities co-occurring with drug resistance and tumor heterogeneity, informing novel therapeutic avenues for KRAS-mutant lung cancer.

Keywords

Cancer therapeutic resistance, Non-small-cell lung cancer, Oncogenes

Rights and Permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

DOI of Published Version

10.1038/s41389-019-0158-7

Source

Oncogenesis. 2019 Aug 20;8(9):45. doi: 10.1038/s41389-019-0158-7. Link to article on publisher's site

Journal/Book/Conference Title

Oncogenesis

Related Resources

Link to Article in PubMed

PubMed ID

31431614

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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