2. Academic Validation
  3. Targeting RICTOR Sensitizes SMAD4-Negative Colon Cancer to Irinotecan

Targeting RICTOR Sensitizes SMAD4-Negative Colon Cancer to Irinotecan

  • Mol Cancer Res. 2020 Mar;18(3):414-423. doi: 10.1158/1541-7786.MCR-19-0525.
Chen Khuan Wong 1 2,  Arthur W Lambert 3,  Sait Ozturk 3,  Panagiotis Papageorgis 4,  Delia Lopez 3,  Ning Shen 5,  Zaina Sen 2,  Hamid M Abdolmaleky 2,  Balázs Győrffy 6 7,  Hui Feng 5,  Sam Thiagalingam 8 2 3 5 9
Affiliations

Affiliations

  • 1 Graduate Program in Genetics and Genomics, Boston University School of Medicine, Boston, Massachusetts.
  • 2 Biomedical Genetics Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
  • 3 Graduate Program in Molecular and Translational Medicine, Boston University School of Medicine, Boston, Massachusetts.
  • 4 Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus.
  • 5 Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts.
  • 6 MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary.
  • 7 Semmelweis University 2nd Department of Pediatrics, Budapest, Hungary.
  • 8 Graduate Program in Genetics and Genomics, Boston University School of Medicine, Boston, Massachusetts. samthia@bu.edu.
  • 9 Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts.
PMID: 31932471 DOI: 10.1158/1541-7786.MCR-19-0525
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.

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