RGD Reference Report - Targeting RICTOR Sensitizes SMAD4-Negative Colon Cancer to Irinotecan. - Rat Genome Database

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Targeting RICTOR Sensitizes SMAD4-Negative Colon Cancer to Irinotecan.

Authors: Wong, Chen Khuan  Lambert, Arthur W  Ozturk, Sait  Papageorgis, Panagiotis  Lopez, Delia  Shen, Ning  Sen, Zaina  Abdolmaleky, Hamid M  Győrffy, Balázs  Feng, Hui  Thiagalingam, Sam 
Citation: Wong CK, etal., Mol Cancer Res. 2020 Mar;18(3):414-423. doi: 10.1158/1541-7786.MCR-19-0525. Epub 2020 Jan 13.
RGD ID: 152995462
Pubmed: PMID:31932471   (View Abstract at PubMed)
PMCID: PMC7115128   (View Article at PubMed Central)
DOI: DOI:10.1158/1541-7786.MCR-19-0525   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
AKT1Humancolon cancer severityIEP mRNA:increased expression:colon (human)RGD 
AKT1Humancolon cancer  IMP human cells in mouse modelRGD 
Akt1Ratcolon cancer severityISOAKT1 (Homo sapiens)mRNA:increased expression:colon (human)RGD 
Akt1Mousecolon cancer  ISOAKT1 (Homo sapiens)human cells in mouse modelRGD 
Akt1Mousecolon cancer severityISOAKT1 (Homo sapiens)mRNA:increased expression:colon (human)RGD 
Akt1Ratcolon cancer  ISOAKT1 (Homo sapiens)human cells in mouse modelRGD 
RICTORHumancolon cancer severityIEP mRNA:increased expression:colon (human)RGD 
RictorRatcolon cancer severityISORICTOR (Homo sapiens)mRNA:increased expression:colon (human)RGD 
RictorMousecolon cancer severityISORICTOR (Homo sapiens)mRNA:increased expression:colon (human)RGD 
SMAD4Humancolon cancer severityIEP mRNA:decreased expression:colon (human)RGD 
Smad4Ratcolon cancer severityISOSMAD4 (Homo sapiens)mRNA:decreased expression:colon (human)RGD 
Smad4Mousecolon cancer severityISOSMAD4 (Homo sapiens)mRNA:decreased expression:colon (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Akt1  (AKT serine/threonine kinase 1)
Rictor  (RPTOR independent companion of MTOR, complex 2)
Smad4  (SMAD family member 4)

Genes (Mus musculus)
Akt1  (thymoma viral proto-oncogene 1)
Rictor  (RPTOR independent companion of MTOR, complex 2)
Smad4  (SMAD family member 4)

Genes (Homo sapiens)
AKT1  (AKT serine/threonine kinase 1)
RICTOR  (RPTOR independent companion of MTOR complex 2)
SMAD4  (SMAD family member 4)

Additional Information