Dietary restriction-resistant human tumors harboring the PIK3CA-activating mutation H1047R are sensitive to metformin
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Sílvia Cufí1,2, Bruna Corominas-Faja1,2, Eugeni Lopez-Bonet3,14, Rosa Bonavia4, Sonia Pernas5,14, Isabel Álvarez López6,14, Joan Dorca2,7,14, Susana Martínez8,14, Norberto Batista López9,14, Severina Domínguez Fernández10,14, Elisabet Cuyàs1,2, Joana Visa4, Esther Rodríguez-Gallego11, Rosa Quirantes-Piné12, Antonio Segura-Carretero12, Jorge Joven11, Begoña Martin-Castillo2,13,14, Javier A. Menendez1,2,14
1 Metabolism & Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia (Spain)
2 Girona Biomedical Research Institute (IDIBGi), Girona, Catalonia (Spain)
3 Department of Anatomical Pathology, Dr. Josep Trueta Hospital of Girona, Girona, Catalonia (Spain)
4 Animal Care Facility, Bellvitge Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Catalonia (Spain)
5 Department of Medical Oncology, Breast Unit, Catalan Institute of Oncology-Hospital Universitari de Bellvitge-Bellvitge Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Catalonia (Spain)
6 Medical Oncology Service, Hospital Donostia, Donostia-San Sebastián, Basque Country (Spain).
7 Department of Medical Oncology, Catalan Institute of Oncology, Girona, Catalonia (Spain)
8 Medical Oncology Department, Hospital de Mataró, Mataró, Barcelona, Catalonia (Spain)
9 Medical Oncology Service, Hospital Universitario de Canarias, La Laguna, Tenerife, Canary Islands (Spain)
10 Medical Oncology Service, Hospital de Txagorritxu, Vitoria-Gasteiz, Araba, Basque Conutry (Spain)
11 Unitat de Recerca Biomèdica (URB-CRB), Institut d’Investigació Sanitaria Pere i Virgili (IISPV), Universitat Rovira i Virgili, Reus, Catalonia (Spain)
12 Department of Analytical Chemistry, Faculty of Sciences, University of Granada, Granada (Spain)
13 Unit of Clinical Research, Catalan Institute of Oncology, Girona, Catalonia (Spain)
14 On behalf of the METTEN-01 Investigators (EudraClinicalTrial Number 2011-000490-30)
Javier A. Menendez, email:
Begoña Martin-Castillo, email:
Keywords: Metformin, cancer, PI3K, PIK3CA mutations, dietary restriction, calorie restriction, rapamycin
Received: August 1, 2013 Accepted: August 19, 2013 Published: August 21, 2013
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.
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