Sorafenib enhances the therapeutic efficacy of rapamycin in colorectal cancers harboring oncogenic KRAS and PIK3CA.
Activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling is associated with tumorigenesis and metastasis of colorectal cancer (CRC). The mammalian target of rapamycin (mTOR) kinase, a downstream effector of PI3K/Akt signaling, regulates tumorigenesis and metastasis of CRCs, indicating that mTOR inhibition may have therapeutic potential. Notwithstanding, many cancers, including CRC, demonstrate resistance to the antitumorigenic effects of rapamycin. In this study, we show that inhibition of mTORC1 with rapamycin leads to feedback activation of PI3K/Akt and Ras-MAPK signaling, resulting in cell survival and possible contribution to rapamycin resistance. Combination with the multikinase inhibitor, sorafenib, abrogates rapamycin-induced activation of PI3K/Akt and Ras-MAPK signaling pathways. Combination of rapamycin with sorafenib synergistically inhibits proliferation of CRC cells. CRCs harboring coexistent KRAS and PIK3CA mutations are partially sensitive to either rapamycin or sorafenib monotherapy, but highly sensitive to combination treatment with rapamycin and sorafenib. Combination with sorafenib enhances therapeutic efficacy of rapamycin on induction of apoptosis and inhibition of cell-cycle progression, migration and invasion of CRCs. We demonstrate efficacy and safety of concomitant treatment with rapamycin and sorafenib at inhibiting growth of xenografts from CRC cells with coexistent mutations in KRAS and PIK3CA. The efficacy and tolerability of combined treatment with rapamycin and sorafenib provides rationale for use in treating CRC patients, particularly those with tumors harboring coexistent KRAS and PIK3CA mutations.
Department of Surgery, University of Kentucky, Lexington, Kentucky, USA.
Pat
P
Gulhati
Yekaterina Y
YY
Zaytseva
Joseph D
JD
Valentino
Payton D
PD
Stevens
Ji Tae
JT
Kim
Takehiko
T
Sasazuki
Senji
S
Shirasawa
Eun Y
EY
Lee
Heidi L
HL
Weiss
Jianli
J
Dong
Tianyan
T
Gao
B Mark
BM
Evers
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000008:administration & dosage*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004357:Drug Synergism; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011506:Proteins / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011725:Pyridines / Q000008:administration & dosage*; D020123:Sirolimus / Q000008:administration & dosage*; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins / Q000235:genetics*
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D058534:Class I Phosphatidylinositol 3-Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009536:Niacinamide; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D011725:Pyridines; D020123:Sirolimus; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C117307:KRAS protein, human; C484760:PIK3CA protein, human