title: Dietary restriction-resistant human tumors harboring the PIK3CA-activating mutation H1047R are sensitive to metformin.
abstract: Cancer cells expressing constitutively active phosphatidylinositol-3 kinase (PI3K) are proliferative regardless of the absence of insulin, and they form dietary restriction (DR)-resistant tumors in vivo. Because the binding of insulin to its receptors activates the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling cascade, activating mutations in the PIK3CA oncogene may determine tumor response to DR-like pharmacological strategies targeting the insulin and mTOR pathways. The anti-diabetic drug metformin is a stereotypical DR mimetic that exerts its anti-cancer activity through a dual mechanism involving insulin-related (systemic) and mTOR-related (cell-autonomous) effects. However, it remains unclear whether PIK3CA-activating mutations might preclude the anti-cancer activity of metformin in vivo. To model the oncogenic PIK3CA-driven early stages of cancer, we used the clonal breast cancer cell line MCF10DCIS.com, which harbors the gain-of-function H1047R hot-spot mutation in the catalytic domain of the PI3KCA gene and has been shown to form DR-refractory xenotumors. To model PIK3CA-activating mutations in late stages of cancer, we took advantage of the isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor using the highly metastatic colorectal cancer cell line SW48. MCF10DCIS.com xenotumors, although only modestly affected by treatment with oral metformin (approximately 40% tumor growth inhibition), were highly sensitive to the intraperitoneal (i.p.) administration of metformin, the anti-cancer activity of which increased in a time-dependent manner and reached >80% tumor growth inhibition by the end of the treatment. Metformin treatment via the i.p. route significantly reduced the proliferation factor mitotic activity index (MAI) and decreased tumor cellularity in MCF10DCIS.com cancer tissues. Whereas SW48-wild-type (PIK3CA+/+) cells rapidly formed metformin-refractory xenotumors in mice, ad libitum access to water containing metformin significantly reduced the growth of SW48-mutated (PIK3CAH1047R/+) xenotumors by approximately 50%. Thus, metformin can no longer be considered as a bona fide DR mimetic, at least in terms of anti-cancer activity, because tumors harboring the insulin-unresponsive, DR-resistant, PIK3CA-activating mutation H1047R remain sensitive to the anti-tumoral effects of the drug. Given the high prevalence of PIK3CA mutations in human carcinomas and the emerging role of PIK3CA mutation status in the treatment selection process, these findings might have a significant impact on the design of future trials evaluating the potential of combining metformin with targeted therapy.
authors.affiliation: Metabolism and Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Cufí
authors.forename: Bruna
authors.initials: B
authors.lastname: Corominas-Faja
authors.forename: Eugeni
authors.initials: E
authors.lastname: Lopez-Bonet
authors.forename: Rosa
authors.initials: R
authors.lastname: Bonavia
authors.forename: Sonia
authors.initials: S
authors.lastname: Pernas
authors.forename: Isabel Álvarez
authors.initials: IÁ
authors.lastname: López
authors.forename: Joan
authors.initials: J
authors.lastname: Dorca
authors.forename: Susana
authors.initials: S
authors.lastname: Martínez
authors.forename: Norberto Batista
authors.initials: NB
authors.lastname: López
authors.forename: Severina Domínguez
authors.initials: SD
authors.lastname: Fernández
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cuyàs
authors.forename: Joana
authors.initials: J
authors.lastname: Visa
authors.forename: Esther
authors.initials: E
authors.lastname: Rodríguez-Gallego
authors.forename: Rosa
authors.initials: R
authors.lastname: Quirantes-Piné
authors.forename: Antonio
authors.initials: A
authors.lastname: Segura-Carretero
authors.forename: Jorge
authors.initials: J
authors.lastname: Joven
authors.forename: Begoña
authors.initials: B
authors.lastname: Martin-Castillo
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D004032:Diet; D005260:Female; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D011897:Random Allocation; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C484760:PIK3CA protein, human