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Article

Mutation-Associated Phenotypic Heterogeneity in Novel and Canonical PIK3CA Helical and Kinase Domain Mutants

Disease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City 1101, Philippines
*
Author to whom correspondence should be addressed.
Present address: MRC Oxford Institute for Radiation Oncology, Department of Oncology, Old Road Campus Research Building, Roosevelt Drive, University of Oxford, Oxford OX3 7DQ, UK.
Cells 2020, 9(5), 1116; https://doi.org/10.3390/cells9051116
Received: 4 March 2020 / Revised: 18 April 2020 / Accepted: 29 April 2020 / Published: 30 April 2020
(This article belongs to the Special Issue PI3K/AKT/mTOR Signaling Network in Human Health and Diseases)
Phosphatidylinositol 3-kinase, catalytic subunit alpha (PIK3CA) is an oncogene often mutated in colorectal cancer (CRC). The contribution of PIK3CA mutations in acquired resistance to anti-epidermal growth factor receptor (EGFR) therapy is well documented, but their prognostic and predictive value remain unclear. Domain- and exon-specific mutations are implicated in either favorable or poor prognoses, but there is paucity in the number of mutations characterized outside of the mutational hotspots. Here, two novel non-hotspot mutants—Q661K in exon 13 and C901R in exon 19—were characterized alongside the canonical exon 9 E545K and exon 20 H1047R mutants in NIH3T3 and HCT116 cells. Q661K and E545K both map to the helical domain, whereas C901R and H1047R map to the kinase domain. Results showed variable effects of Q661K and C901R on morphology, cellular proliferation, apoptosis resistance, and cytoskeletal reorganization, with both not having any effect on cellular migration. In comparison, E545K markedly promoted proliferation, survival, cytoskeletal reorganization, migration, and spheroid formation, whereas H1047R only enhanced the first three. In silico docking suggested these mutations negatively affect binding of the p85 alpha regulatory subunit to PIK3CA, thereby relieving PIK3CA inhibition. Altogether, these findings support intra-domain and mutation-specific variability in oncogenic readouts, with implications in degree of aggressiveness. View Full-Text
Keywords: PIK3CA; colorectal cancer; EGFR pathway; tumor heterogeneity PIK3CA; colorectal cancer; EGFR pathway; tumor heterogeneity
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MDPI and ACS Style

Ghodsinia, A.A.; Lego, J.-A.M.T.; Garcia, R.L. Mutation-Associated Phenotypic Heterogeneity in Novel and Canonical PIK3CA Helical and Kinase Domain Mutants. Cells 2020, 9, 1116. https://doi.org/10.3390/cells9051116

AMA Style

Ghodsinia AA, Lego J-AMT, Garcia RL. Mutation-Associated Phenotypic Heterogeneity in Novel and Canonical PIK3CA Helical and Kinase Domain Mutants. Cells. 2020; 9(5):1116. https://doi.org/10.3390/cells9051116

Chicago/Turabian Style

Ghodsinia, Arman A., J-Ann M.T. Lego, and Reynaldo L. Garcia 2020. "Mutation-Associated Phenotypic Heterogeneity in Novel and Canonical PIK3CA Helical and Kinase Domain Mutants" Cells 9, no. 5: 1116. https://doi.org/10.3390/cells9051116

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