Targeting RICTOR sensitizes SMAD4-negative colon cancer to irinotecan

Chen Khuan Wong, Arthur W. Lambert, Sait Ozturk, Panagiotis Papageorgis, Delia Lopez, Ning Shen, Zaina Sen, Hamid M. Abdolmaleky, Balázs Gyorffy, Hui Feng, Sam Thiagalingam

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish
Pages (from-to)414-423
Number of pages10
JournalMolecular Cancer Research
Volume18
Issue number3
DOIs
StatePublished - 2020
Externally publishedYes

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