miR-1298 Inhibits Mutant KRAS-Driven Tumor Growth by Repressing FAK and LAMB3
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Abstract
Global miRNA functional screens can offer a strategy to identify synthetic lethal interactions in cancer cells that might be exploited therapeutically. In this study, we applied this strategy to identify novel gene interactions in KRAS-mutant cancer cells. In this manner, we discovered miR-1298, a novel miRNA that inhibited the growth of KRAS-driven cells both in vitro and in vivo. Using miR-TRAP affinity purification technology, we identified the tyrosine kinase FAK and the laminin subunit LAMB3 as functional targets of miR-1298. Silencing of FAK or LAMB3 recapitulated the synthetic lethal effects of miR-1298 expression in KRAS-driven cancer cells, whereas coexpression of both proteins was critical to rescue miR-1298–induced cell death. Expression of LAMB3 but not FAK was upregulated by mutant KRAS. In clinical specimens, elevated LAMB3 expression correlated with poorer survival in lung cancer patients with an oncogenic KRAS gene signature, suggesting a novel candidate biomarker in this disease setting. Our results define a novel regulatory pathway in KRAS-driven cancers, which offers a potential therapeutic target for their eradication. Cancer Res; 76(19); 5777–87. ©2016 AACR.
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FAK acts downstream of KRAS, and its inhibition is effective in suppressing the progression of KRAS mutant cancer.
“FAK acts downstream of KRAS, and its inhibition is effective in suppressing the progression of KRAS mutant cancer.[ 12, 13, 14 ]”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [13]
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References 39 · Cited by 54
- Authors
- Zhou, Y., Dang, J., Chang, K.-Y., Yau, E., Aza-Blanc, P., Moscat, J., & Rana, T. M.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- University of California San Diego (US)
- 1Program for RNA Biology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
- Corresponding author
- Rana, Tariq M.
- Venue
- Cancer Research
- Published
- 2016-10-01
- Volume
- 76
- Issue
- 19
- Pages
- 5777-5787
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC5155639
- OpenAlex
- W2528878150
- Cited by
- 54
- References
- 39
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2022: 2 · 2021: 10 · 2020: 7 · 2019: 8 · 2018: 10 · 2017: 6
- FWCI
- 3.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Drug Abuse (DP1DA039562)
- National Cancer Institute (P01CA177322)
- National Institute of Allergy and Infectious Diseases (R01AI043198, R01AI041404)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- KRAS mutation, synthetic lethality, focal adhesion kinase, LAMB3, microRNA target regulation, lung cancer, prognostic factors, tumor growth inhibition, therapeutic target
- MeSH terms
- Kalinin, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Cell Adhesion Molecules, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), MicroRNAs, Cell Line, Tumor, Focal Adhesion Protein-Tyrosine Kinases
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