Cancer treatments using combinations of PI3K/Akt pathway and ERK inhibitors
The present invention provides, inter alia, methods, kits, and compositions for treating or ameliorating the effects of a cancer in a subject in need thereof. This method includes administering to the subject an effective amount of (i) a first anti-cancer agent, which is BVD-523 or a pharmaceutically acceptable salt thereof and (ii) a second anti-cancer agent, which is an inhibitor of the PI3K/Akt pathway or a pharmaceutically acceptable salt thereof. Also provided are methods of treating or ameliorating the effects of a subject with cancer in which the subject has a somatic KRAS and a somatic PIK3CA mutation or in which the cancer is refractory to a therapy selected from RAF inhibitor therapy, MEK inhibitor therapy, and RAF and MEK inhibitor therapy.
1. A method of treating or ameliorating the effects of a cancer in a subject in need thereof comprising administering to the subject an effective amount of (i) a first anti-cancer agent, which is BVD-523 or a pharmaceutically acceptable salt thereof and (ii) a second anti-cancer agent, which is an inhibitor of the PI3K/Akt pathway or a pharmaceutically acceptable salt thereof, to treat or ameliorate the effects of the cancer,
wherein the inhibitor of the PI3K/Akt pathway is selected from the group consisting of BYL719, BKM120, PF-04691502, pharmaceutically acceptable salts thereof, and combinations thereof, and
wherein administration of the first and second anti-cancer agents provides a synergistic effect compared to administration of either anti-cancer agent alone.
2. The method according to claim 1 , wherein the subject is a mammal.
3. The method according to claim 2 , wherein the mammal is selected from the group consisting of humans, primates, farm animals, and domestic animals.
4. The method according to claim 2 , wherein the mammal is a human.
5. The method according to claim 1 , wherein the subject with cancer has a somatic KRAS mutation or is refractory to MAPK pathway inhibitor treatment.
6. The method according to claim 5 , wherein the subject with cancer has a somatic KRAS mutation and a somatic PIK3CA mutation.
7. The method according to claim 5 , wherein the cancer is selected from the group consisting of a cancer of the large intestine, breast cancer, liver cancer, colon cancer, pancreatic cancer, endometrial cancers, stomach cancer, lung cancer, and leukemia.
8. The method according to claim 5 , wherein the cancer is colon cancer.
9. The method according to claim 1 further comprising administering at least one additional therapeutic agent selected from the group consisting of an antibody or fragment thereof, a cytotoxic agent, a drug, a toxin, a radionuclide, an immunomodulator, a photoactive therapeutic agent, a radiosensitizing agent, a hormone, an anti-angiogenesis agent, and combinations thereof.
10. The method according to claim 9 , wherein the additional therapeutic agent is an inhibitor of the mTOR pathway.
11. The method according to claim 10 , wherein the inhibitor of the mTOR pathway is selected from the group consisting of zotarolimus, umirolimus, temsirolimus, sirolimus, sirolimus NanoCrystal, everolimus, biolimus A9, ridaforolimus, rapamycin, TCD-10023, DE-109, MS R001, MS R002, MS-R003, (−)-rapamycin, XL-765, quinacrine, PKI-587, PF-04691502, GDC-0980, dactolisib, CC-223, PWT-33597, P-7170, LY-3023414, INK-128, GDC-0084, DS-7423, DS-3078, CC-115, CBLC-137, AZD-2014, X-480, X-414, EC-0371, VS-5584, PQR-401, PQR-316, PQR-311, PQR-309, PF-06465603, NV-128, nPT-MTOR, BC-210, WAY-600, WYE-354, WYE-687, LOR-220, HMPL-518, GNE-317, EC-0565, CC-214, ABTL-0812, and pharmaceutically acceptable salts thereof, and combinations thereof.
12. A method of effecting cancer cell death comprising contacting the cancer cell with an effective amount of (i) a first anti-cancer agent, which is BVD-523 or a pharmaceutically acceptable salt thereof and (ii) a second anti-cancer agent, which is a an inhibitor of the PI3K/Akt pathway or a pharmaceutically acceptable salt thereof,
wherein the inhibitor of the PI3K/Akt pathway is selected from the group consisting of BYL719, BKM120, PF-04691502, pharmaceutically acceptable salts thereof, and combinations thereof, and
wherein administration of the first and second anti-cancer agents provides a synergistic effect compared to administration of either anti-cancer agent alone.
13. The method according to claim 12 , wherein the cancer cell is mammalian cancer cell.
14. The method according to claim 13 , wherein the mammalian cancer cell is obtained from a mammal selected from the group consisting of humans, primates, farm animals, and domestic animals.
15. The method according to claim 13 , wherein the mammalian cancer cell is a human cancer cell.
16. The method according to claim 12 , wherein the subject with cancer has a somatic KRAS mutation or is refractory to MAPK pathway inhibitor treatment.
17. The method according to claim 16 , wherein the subject with cancer has a somatic KRAS mutation and a somatic PIK3CA mutation.
18. The method according to claim 16 , wherein the cancer is selected from the group consisting of a cancer of the large intestine, breast cancer, liver cancer, colon cancer, pancreatic cancer, endometrial cancers, stomach cancer, lung cancer, and leukemia.
19. The method according to claim 16 , wherein the cancer is colon cancer.
20. The method according to claim 12 further comprising contacting the cancer cell with at least one additional therapeutic agent selected from the group consisting of an antibody or fragment thereof, a cytotoxic agent, a drug, a toxin, a radionuclide, an immunomodulator, a photoactive therapeutic agent, a radiosensitizing agent, a hormone, an anti-angiogenesis agent, and combinations thereof.
21. The method according to claim 20 , wherein the additional therapeutic agent is an inhibitor of the mTOR pathway.
22. The method according to claim 21 , wherein the inhibitor of the mTOR pathway is selected from the group consisting of zotarolimus, umirolimus, temsirolimus, sirolimus, sirolimus NanoCrystal, everolimus, biolimus A9, ridaforolimus, rapamycin, TCD-10023, DE-109, MS-R001, MS-R002, MS-R003, (−)-rapamycin, XL-765, quinacrine, PKI-587, PF-04691502, GDC-0980, datolisib, CC-223, PWT-33597, P-7170, LY-3023414, INK-128, GDC 0084, DS-7423, DS-3078, CC-115, CBLC-137, AZD-2014, X-480, X-414, EC-0371, VS-5584, PQR-401, PQR-316, PQR-311, PQR-309, PF-06465603, NV-128, nPT MTOR, BC-210, WAY-600, WYE-354, WYE-687, LOR-220, HMPL-518, GNE-317, EC-0565, CC-214, ABTL-0812, and pharmaceutically acceptable salts thereof, and combinations thereof.