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Dietary restriction-resistant human tumors harboring the PIK3CA-activating mutation H1047R are sensitive to metformin.

Cufí S, Corominas-Faja B, Lopez-Bonet E, Bonavia R, Pernas S, López IÁ, Dorca J, Martínez S, López NB, Fernández SD, Cuyàs E, Visa J, Rodríguez-Gallego E, Quirantes-Piné R, Segura-Carretero A, Joven J, Martin-Castillo B, Menendez JA - Oncotarget (2013)

Bottom Line: 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.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%.

View Article: PubMed Central - PubMed

Affiliation: Metabolism and Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia, Spain.

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.

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Isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor promotes sensitization to the anti-cancer effects of metformin. Shown are the mean tumor volumes (±SD) of SW48-WT (left panel) and SW48-Mut (right panel) xenograft-bearing nude mice following oral (ad libitum access to water containing 250 mg kg−1 metformin) administration of metformin for ∼5 weeks. Tumor growth rates were significantly different between the control and the oral metformin groups in SW48-Mut xenografts (* Student's t-test P<0.01).
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Figure 3: Isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor promotes sensitization to the anti-cancer effects of metformin. Shown are the mean tumor volumes (±SD) of SW48-WT (left panel) and SW48-Mut (right panel) xenograft-bearing nude mice following oral (ad libitum access to water containing 250 mg kg−1 metformin) administration of metformin for ∼5 weeks. Tumor growth rates were significantly different between the control and the oral metformin groups in SW48-Mut xenografts (* Student's t-test P<0.01).

Mentions: Isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor promotes sensitization to the anti-cancer effects of metformin. To model PIK3CA-activating mutations in the late stages of human cancer, we used two types of cancer cells derived from the highly metastatic SW48 colorectal cancer cell line. These cell lines were isogenic, except that one line (SW48-WT) carries a wild-type allele of the PIK3CA oncogene, and the other (SW48-Mut) carries a constitutively active mutant allele (H1047R). In xenograft studies, the subcutaneous injection of SW48-WT or SW48-Mut cells into nude mice yielded tumors of approximately equal volume within 27 days (Fig. 3, left panel). The administration of an oral regimen of metformin to xenografted mice beginning 1 week before tumor cell injection failed to significantly alter tumor size in SW48-WT xenotumors over time. In contrast, SW48-Mut cells formed metformin-sensitive tumors that showed significant decreases in tumor volume under the metformin feeding condition. Compared with the mean xenograft tumor volume (1138±188 mm3) in the untreated control animals, oral treatment with metformin resulted in a notable reduction in the mean tumor volume, to 572±134 mm3 (Fig. 3, right panel). Indeed, the inhibitory effect of oral metformin against SW48-Mut xenotumors increased in a time-dependent manner, reaching a maximum of approximately 50% at 21 days after cell inoculation.


Dietary restriction-resistant human tumors harboring the PIK3CA-activating mutation H1047R are sensitive to metformin.

Cufí S, Corominas-Faja B, Lopez-Bonet E, Bonavia R, Pernas S, López IÁ, Dorca J, Martínez S, López NB, Fernández SD, Cuyàs E, Visa J, Rodríguez-Gallego E, Quirantes-Piné R, Segura-Carretero A, Joven J, Martin-Castillo B, Menendez JA - Oncotarget (2013)

Isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor promotes sensitization to the anti-cancer effects of metformin. Shown are the mean tumor volumes (±SD) of SW48-WT (left panel) and SW48-Mut (right panel) xenograft-bearing nude mice following oral (ad libitum access to water containing 250 mg kg−1 metformin) administration of metformin for ∼5 weeks. Tumor growth rates were significantly different between the control and the oral metformin groups in SW48-Mut xenografts (* Student's t-test P<0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824528&req=5

Figure 3: Isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor promotes sensitization to the anti-cancer effects of metformin. Shown are the mean tumor volumes (±SD) of SW48-WT (left panel) and SW48-Mut (right panel) xenograft-bearing nude mice following oral (ad libitum access to water containing 250 mg kg−1 metformin) administration of metformin for ∼5 weeks. Tumor growth rates were significantly different between the control and the oral metformin groups in SW48-Mut xenografts (* Student's t-test P<0.01).
Mentions: Isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor promotes sensitization to the anti-cancer effects of metformin. To model PIK3CA-activating mutations in the late stages of human cancer, we used two types of cancer cells derived from the highly metastatic SW48 colorectal cancer cell line. These cell lines were isogenic, except that one line (SW48-WT) carries a wild-type allele of the PIK3CA oncogene, and the other (SW48-Mut) carries a constitutively active mutant allele (H1047R). In xenograft studies, the subcutaneous injection of SW48-WT or SW48-Mut cells into nude mice yielded tumors of approximately equal volume within 27 days (Fig. 3, left panel). The administration of an oral regimen of metformin to xenografted mice beginning 1 week before tumor cell injection failed to significantly alter tumor size in SW48-WT xenotumors over time. In contrast, SW48-Mut cells formed metformin-sensitive tumors that showed significant decreases in tumor volume under the metformin feeding condition. Compared with the mean xenograft tumor volume (1138±188 mm3) in the untreated control animals, oral treatment with metformin resulted in a notable reduction in the mean tumor volume, to 572±134 mm3 (Fig. 3, right panel). Indeed, the inhibitory effect of oral metformin against SW48-Mut xenotumors increased in a time-dependent manner, reaching a maximum of approximately 50% at 21 days after cell inoculation.

Bottom Line: 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.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%.

View Article: PubMed Central - PubMed

Affiliation: Metabolism and Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia, Spain.

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.

Show MeSH
Related in: MedlinePlus