Emerging strategies to target the dysfunctional cohesin complex in cancer

ABSTRACT

Introduction: Mutations in cohesin genes have been described in numerous solid cancers and hematologic malignancies; subsequent experimental evidence has linked these mutations with carcinogenesis.

Areas covered: In this review, we present current information about the physiological role of the cohesin complex in normal and malignant cells and describe current therapeutic strategies that are being explored in cohesin-mutated cancers. We discuss a range of targets and strategies that should be explored to develop targeted therapies for patients with aberrant cohesin.

Expert opinion: Targeting of the cohesin complex is an underexplored area of drug development. There is a high frequency of cohesin mutations in multiple cancers, hence specific targeting strategies should be explored. Cohesins play a crucial role in cellular organization; therefore, we expect a narrow therapeutic window of direct inhibitors of cohesin components. Exploiting experimental approaches that correct dysfunctional cohesins and coupling them with current therapeutic strategies can provide novel, innovative and more effective treatment regimens.

Trial registration: ClinicalTrials.gov identifier: NCT00111683.

Trial registration: ClinicalTrials.gov identifier: NCT00405054.

Trial registration: ClinicalTrials.gov identifier: NCT01145989.

Trial registration: ClinicalTrials.gov identifier: NCT00898287.

Trial registration: ClinicalTrials.gov identifier: NCT00882063.

KEYWORDS:

• Cohesin
• cancer
• therapeutics
• synthetic lethality
• small molecule inhibitors
• antisense oligonucleotides

Article Highlights

• The cohesin complex ensures the physiological distribution of sister chromatids during cell division and participates in other important cell mechanisms such as gene regulation.

• Mutations in cohesin genes have been identified in a plethora of cancers and certain developmental disorders.

• STAG2 is the most frequently mutated cohesin gene in solid cancers, while STAG1, STAG2, RAD21, SMC1A, and SMC3 are found mutated in hematologic malignancies.

• Chromosomal aberrations or dysregulated gene expression due to mutated cohesins contribute to carcinogenesis.

• Experimental evidence has shown that targeting the cohesin complex or its regulators can reduce tumor burden in different ways such as sensitizing cancer cells to chemotherapy.

We propose that cohesin mutated patients are considered as a distinct subgroup in clinical trials and that targeted agents like PLK1 and PARP-inhibitors are evaluated in this patient subgroup.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The paper was not funded. This author’s research is funded by The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) grant 5240/6-2.