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Advances and Insights of APC-Asef Inhibitors for Metastatic Colorectal Cancer Therapy.

ABSTRACT: In Colorectal cancer (CRC), adenomatous polyposis coli (APC) directly interacts with the Rho guanine nucleotide exchange factor 4 (Asef) and releases its GEF activity. Activated Asef promotes the aberrant migration and invasion of CRC cell through a CDC42-mediated pathway. Knockdown of either APC or Asef significantly decreases the migration of CRC cells. Therefore, disrupting the APC-Asef interaction is a promising strategy for the treatment of invasive CRC. With the growth of structural information, APC-Asef inhibitors have been designed, providing hope for CRC therapy. Here, we will review the APC-Asef interaction in cancer biology, the structural complex of APC-Asef, two generations of peptide inhibitors of APC-Asef, and small molecule inhibitors of APC-Asef, focusing on research articles over the past 30 years. We posit that these advances in the discovery of APC-Asef inhibitors establish the protein-protein interaction (PPI) as targetable and provide a framework for other PPI programs.

SUBMITTER: Yang X

PROVIDER: S-EPMC8100458 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe prognostic implication of wild-type APC (APC-WT) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is not well defined.Materials and methodsAPC prognostic value was evaluated retrospectively in two independent cohorts of patient with MSS mCRC with a confirmatory analysis from a public data set from Memorial Sloan Kettering Cancer Center (MSKCC).ResultsIn comparison with the APC-mutant (APC-MT) population (n = 255), APC-WT patients (n = 86) tended to be younger (59% of age < 40 vs. 26% of age > 50), right-sided (41.7% vs. 27%), BRAFV600E mutated (23.3% vs. 0.8%), and KRAS wild type (65.1% vs. 49.8%). Alternative WNT pathway alterations, RNF43 and CTNNB1, were over-represented in the APC-WT versus APC-MT population (7% vs. 0.4% and 4.7% vs. 0.4%, respectively). APC-WT patients had a worse overall survival (OS) than APC-MT patients (22.6 vs. 45.6 months, p < .0001). Using a multivariate model correcting for primary tumor location, RAS and BRAF status, APC-WT was predictive of poor survival (APC-MT vs. APC-WT, hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.44-0.86, p = .0037). The prognostic implication of APC-WT on OS was confirmed further in a similar multivariate model of 934 stage IV patients from MSKCC public database (APC-MT vs. APC-WT, HR, 0.63, 95% CI, 0.49-0.81, p < .0001).ConclusionAPC-WT is associated with poor OS in MSS mCRC regardless of RAS and BRAF status. Compared with APC-MT mCRC tumors, APC-WT tumors were associated with other Wnt activating alterations, including RNF43 and CTNBB1. Our data suggest alternative therapy needs to be investigated in APC-WT patients.Implications for practicePatients with microsatellite stable metastatic colorectal cancer with wild-type APC had a worse overall survival than patients with mutated APC regardless of RAS/RAF status. APC status should be considered as a stratification factor in prospective trials, and novel therapeutic strategies need to be developed for this subgroup of patients.

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Advances and Insights of APC-Asef Inhibitors for Metastatic Colorectal Cancer Therapy.

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