PIK3CA Mutation Uncouples Tumor Growth and Cyclin D1 Regulation from MEK/ERK and Mutant KRAS Signaling
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Abstract
Mutational activation of KRAS is a common event in human tumors. Identification of the key signaling pathways downstream of mutant KRAS is essential for our understanding of how to pharmacologically target these cancers in patients. We show that PD0325901, a small-molecule MEK inhibitor, decreases MEK/ERK pathway signaling and destabilizes cyclin D1, resulting in significant anticancer activity in a subset of KRAS mutant tumors in vitro and in vivo. Mutational activation of PIK3CA, which commonly co-occurs with KRAS mutation, provides resistance to MEK inhibition through reactivation of AKT signaling. Genetic ablation of the mutant PIK3CA allele in MEK inhibitor–resistant cells restores MEK pathway sensitivity, and re-expression of mutant PIK3CA reinstates the resistance, highlighting the importance of this mutation in resistance to therapy in human cancers. In KRAS mutant tumors, PIK3CA mutation restores cyclin D1 expression and G1-S cell cycle progression so that they are no longer dependent on KRAS and MEK/ERK signaling. Furthermore, the growth of KRAS mutant tumors with coexistent PIK3CA mutations in vivo is profoundly inhibited with combined pharmacologic inhibition of MEK and AKT. These data suggest that tumors with both KRAS and phosphoinositide 3-kinase mutations are unlikely to respond to the inhibition of the MEK pathway alone but will require effective inhibition of both MEK and phosphoinositide 3-kinase/AKT pathway signaling. Cancer Res; 70(17); 6804–14. ©2010 AACR.
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Inhibition of the growth of tumors in which ERK and PI3K/mTOR signaling are dysregulated requires inhibition of both pathways.
“Nevertheless, these data are consistent with our previous findings that inhibition of the growth of tumors in which ERK and PI3K/mTOR signaling are dysregulated requires inhibition of both pathways15,24.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [24]
The Results section reports that combined MEK and AKT inhibition profoundly suppressed growth of KRAS/PIK3CA-mutant tumor xenografts, whereas either inhibitor alone had no significant effect. The claim extends this finding to tumors with dysregulated ERK and PI3K/mTOR signaling generally; this paper's reported result is narrower and concerns PI3K/AKT signaling, not specifically mTOR. Page numbers are not provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSeveral downstream processes are under the control of both ERK and PI3K/mTOR signaling and their effective inhibition requires inhibition of both pathways.
“We have previously shown that several downstream processes are under the control of both ERK and PI3K/mTOR signaling and that their effective inhibition requires inhibition of both pathways15,24.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [24]
The Results (page not provided) show that combined MEK and AKT inhibition suppressed growth and induced apoptosis in KRAS/PIK3CA-mutant tumor xenografts when either inhibitor alone did not. The Discussion proposes that ERK and PI3K/AKT converge on processes including survival, translation and cell-cycle regulation, but presents those additional targets as possibilities. The paper does not establish that several such processes require dual inhibition, and it studies PI3K/AKT rather than specifically PI3K/mTOR signaling. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe PI3K/AKT/mTOR and RAS/RAF/ERK pathways converge on key cellular processes, including Cyclin D-Cdk4/6 activation and cap-dependent translation, and both pathways must be inhibited to affect tumor growth or survival.
“We have previously shown that the PI3K/AKT/mTOR and RAS/RAF/ERK pathways converge on key cellular processes, including Cyclin D-Cdk4/6 activation and cap-dependent translation and that both pathways must be inhibited to affect tumor growth or survival15,24.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [24]
The Discussion proposes that PI3K/AKT and ERK signaling converge on targets involved in protein translation and the cell cycle, including Cyclin D1; it does not specifically establish cap-dependent translation or Cyclin D–Cdk4/6 activation. The Results find that combined inhibition suppresses growth and induces apoptosis in xenografts with both KRAS and PIK3CA mutations. The Discussion also says some tumors may respond to MEK inhibition alone, so the claim that both pathways must always be inhibited is too broad. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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- Authors
- Halilovic, E., She, Q.-B., Ye, Q., Pagliarini, R., Sellers, W. R., Solit, D. B., & Rosen, N.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Rosen, Neal
- ORCID
- Venue
- Cancer Research
- Published
- 2010-08-31
- Volume
- 70
- Issue
- 17
- Pages
- 6804-6814
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3178450
- OpenAlex
- W2122476809
- Cited by
- 168
- References
- 40
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 9 · 2023: 5 · 2022: 4 · 2021: 7 · 2020: 7 · 2019: 10 · 2018: 3 · 2017: 9 · 2016: 13 · 2015: 12 · 2014: 13 · 2013: 24 · 2012: 26
- FWCI
- 8.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01CA129243, R01CA127240, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- PIK3CA mutation, KRAS mutation, MEK/ERK signaling, MEK inhibitor resistance, PD0325901, cyclin D1, Akt signaling, phosphatidylinositol 3-kinase, combination therapy, G1/S cell cycle progression, tumor growth
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Alleles, Animals, Benzamides, Colonic Neoplasms, Diphenylamine, Humans, Lung Neoplasms, Mutation, Pancreatic Neoplasms, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), ras Proteins, Phosphatidylinositol 3-Kinases, Cyclin D1, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, HCT116 Cells, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, Cell Growth Processes, Proto-Oncogene Proteins c-akt, Mice, Gene Knockout Techniques, Class I Phosphatidylinositol 3-Kinases
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