HSP90/AXL/eIF4E-regulated unfolded protein response as an acquired vulnerability in drug-resistant KRAS-mutant lung cancer
Open accessAbstract
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.
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HSP90 inhibitors synergistically enhance antitumor effects of pemetrexed and MEK inhibitors in multiple in vitro and in vivo models.
“In line with these mechanistic findings, HSP90 inhibitors synergistically enhance antitumor effects of pemetrexed and MEK inhibitors in multiple in vitro and in vivo models, validating a rational combination strategy to treat KRAS-mutant lung cancer.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [86]
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New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness
Yang, H., Liang, S.-Q., Schmid, R. A., & Peng, R.-W. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00953 · Cited by 129 · see citing works
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- Authors
- Yang, H., Liang, S.-Q., Xu, D., Yang, Z., Marti, T. M., Gao, Y., Kocher, G. J., Zhao, H., Schmid, R. A., & Peng, R.-W.
- Affiliations
- University of Bern (CH)
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Schmid, Ralph A.
- Peng, Ren-Wang
- ORCID
- Venue
- Oncogenesis
- Published
- 2019-08-20
- Volume
- 8
- Issue
- 9
- Pages
- 45-45
- ISSN
- 2157-9024 (ISSN-L)
- PMC
- PMC6702198
- OpenAlex
- W2969509842
- Cited by
- 58
- References
- 47
- Citations by year
- 2026: 7 · 2025: 3 · 2024: 6 · 2023: 7 · 2022: 11 · 2021: 15 · 2020: 7 · 2019: 2
- FWCI
- 6.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Oncogenesis (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Open Access CRIS of the University of Bern
- Funders
- Bernische Krebsliga
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS-mutant lung cancer, drug resistance, unfolded protein response, endoplasmic reticulum stress, HSP90, AXL, eIF4E, pemetrexed, trametinib, intratumoral heterogeneity, combination therapy, Hsp90 inhibitors
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