PIK3CAH1047R Accelerates and Enhances KRASG12D-Driven Lung Tumorigenesis
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Abstract
KRAS-activating mutations drive human non–small cell lung cancer and initiate lung tumorigenesis in genetically engineered mouse (GEM) models. However, in a GEM model of KRASG12D-induced lung cancer, tumors arise stochastically following a latency period, suggesting that additional events are required to promote early-stage tumorigenic expansion of KRASG12D-mutated cells. PI3Kα (PIK3CA) is a direct effector of KRAS, but additional activation of PI3′-lipid signaling may be required to potentiate KRAS-driven lung tumorigenesis. Using GEM models, we tested whether PI3′-lipid signaling was limiting for the promotion of KRASG12D-driven lung tumors by inducing the expression of KRASG12D in the absence and presence of the activating PIK3CAH1047R mutation. PIK3CAH1047R expression alone failed to promote tumor formation, but dramatically enhanced tumorigenesis initiated by KRASG12D. We further observed that oncogenic cooperation between KRASG12D and PIK3CAH1047R was accompanied by PI3Kα-mediated regulation of c-MYC, GSK3β, p27KIP1, survivin, and components of the RB pathway, resulting in accelerated cell division of human or mouse lung cancer–derived cell lines. These data suggest that, although KRASG12D may activate PI3Kα by direct biochemical mechanisms, PI3′-lipid signaling remains rate-limiting for the cell-cycle progression and expansion of early-stage KRASG12D-initiated lung cells. Therefore, we provide a potential mechanistic rationale for the selection of KRAS and PIK3CA coactivating mutations in a number of human malignancies, with implications for the clinical deployment of PI3′ kinase–targeted therapies. Cancer Res; 75(24); 5378–91. ©2015 AACR.
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Several KRAS alleles had reduced comutation with NRAS and BRAF, and increased comutation with APC and PIK3CA.
“Several KRAS alleles had reduced comutation with NRAS and BRAF, and increased comutation with APC and PIK3CA”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [47]
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Concurrent PIK3CA mutant drives cachexia through inflammatory signaling in EGFR mutant lung cancerPreprint
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- Authors
- Green, S., Trejo, C. L., & McMahon, M.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- McMahon, Martin
- Venue
- Cancer Research
- Published
- 2015-12-14
- Volume
- 75
- Issue
- 24
- Pages
- 5378-5391
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4681648
- OpenAlex
- W2172561271
- Cited by
- 38
- References
- 53
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 3 · 2023: 4 · 2021: 5 · 2020: 1 · 2019: 5 · 2018: 4 · 2017: 7 · 2016: 1
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Genentech
- National Cancer Institute (R01CA131261)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- PIK3CA H1047R, KRAS G12D, lung carcinogenesis, non-small cell lung cancer, PI3Kα, oncogene cooperation, c-Myc, GSK3β, p27, survivin, retinoblastoma pathway, cell cycle progression, genetically engineered mouse models
- MeSH terms
- Animals, Carcinoma, Non-Small-Cell Lung, Cell Transformation, Neoplastic, Disease Models, Animal, Humans, Immunohistochemistry, Lung Neoplasms, Mice, Mutant Strains, Immunoblotting, Signal Transduction, Proto-Oncogene Proteins p21(ras), Phosphatidylinositol 3-Kinases, Mice, Class I Phosphatidylinositol 3-Kinases, Carcinogenesis
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