Targeting RICTOR Sensitizes SMAD4-Negative Colon Cancer to Irinotecan

Abstract

Deciphering molecular targets to enhance sensitivity to chemotherapy is becoming a priority for effectively treating cancers. Loss of function mutations of SMAD4 in colon cancer are associated with metastatic progression and resistance to 5-fluorouracil (5-FU), the most extensively used drug of almost all chemotherapy combinations used in the treatment of metastatic colon cancer. Here, we report that SMAD4 deficiency also confers resistance to irinotecan, another common chemotherapeutic frequently used alone or in combination with 5-FU against colon cancer. Mechanistically, we find that SMAD4 interacts with and inhibits RICTOR, a component of the mTORC2 complex, resulting in suppression of downstream effector phosphorylation of AKT at Serine 473. In silico meta-analysis of publicly available gene expression datasets derived from tumors indicates that lower levels of SMAD4 or higher levels of RICTOR/AKT, irrespective of the SMAD4 status, correlate with poor survival, suggesting them as strong prognostic biomarkers and targets for therapeutic intervention. Moreover, we find that overexpression of SMAD4 or depletion of RICTOR suppresses AKT signaling and increases sensitivity to irinotecan in SMAD4-deficient colon cancer cells. Consistent with these observations, pharmacologic inhibition of AKT sensitizes SMAD4-negative colon cancer cells to irinotecan in vitro and in vivo. Overall, our study suggests that hyperactivation of the mTORC2 pathway is a therapeutic vulnerability that could be exploited to sensitize SMAD4-negative colon cancer to irinotecan.Implications: Hyperactivation of the mTORC2 pathway in SMAD4-negative colon cancer provides a mechanistic rationale for targeted inhibition of mTORC2 or AKT as a distinctive combinatorial therapeutic opportunity with chemotherapy for colon cancer.

Role of mammalian target of rapamycin complex 2 in primary and secondary liver cancer

“…Reita et al [ 84 ] demonstrated that the combination of irinotecan and a mTORC1/2 blocker reduced migration and invasion in vitro as well as the development of liver metastases in vivo more effectively than irinotecan alone. Consistently, the knockdown of Rictor increased the sensitivity to irinotecan in SMAD4-negative colon cancer cells[ 85 ].…”

Targeting Akt in cancer for precision therapy

“… [ 248 ] CBL mutation Myeloid neoplasmas [ 249 ] BTK mutation or deficiency Follicular lymphoma [ 253 ] GPS2 mutation Breast cancer, medulloblastoma [ 250 – 252 ] CDH1 mutation or deficiency Gastric cancer, breast cancer, prostate cancer, colorectal cancer, ovarian cancer, etc. [ 261 , 262 ] SMAD4 mutation Colorectal cancer, pancreatic cancer [ 269 , 270 ] GAB2 mutation or amplification Hematological malignancies, ovarian cancer, lung cancer, neuroblastoma, melanoma, breast cancer [ 264 – 268 ] …”

“…Hence, it warrants further studies to determine if Akt inhibitors may effectively treat GAB2 mutant-associated hematological malignancies and GAB2-amplified cancers. In addition, mothers against decapentaplegic homolog 4 (SMAD4) interacts with rictor and prevents the phosphorylation of Akt by mTORC2 [ 269 ]. Hence, loss-of-function SMAD4 mutations, which are present in some types of tumors such as mucinous adenocarcinoma of the colon and pancreatic carcinoma [ 270 ], may lead to Akt activation.…”

“…Hence, loss-of-function SMAD4 mutations, which are present in some types of tumors such as mucinous adenocarcinoma of the colon and pancreatic carcinoma [ 270 ], may lead to Akt activation. SMAD4-deficient colon cancer may be vulnerable to combined treatment with Akt inhibitors and irinotecan [ 269 ]. Finally, germline mutations of SAMD4 are associated with juvenile polyposis syndrome [ 271 , 272 ].…”

Molecular features and gene expression signature of metastatic colorectal cancer (Review)

“…SMAD4 interacts with RICTOR to suppress mTORC2 functionality and therefore the loss of SMAD4 function results in oncogenic activation of the mTORC2 pathway, leading to enhancement in metastatic colon cancer progression. Overactivation of mTORC1 can promote tumour formation, proliferation, and metastasis, while mTORC2 can regulate the expression of mTORC1 through the mTORC2/AKT pathway ( 126 , 127 ).…”