Cytoskeletal and mitotic partners for synthetic lethal targeting of E-cadherin-deficient carcinoma

Abstract

Hereditary diffuse gastric cancer (HDGC) is the familial predisposition to poorly-differentiated, diffuse gastric adenocarcinoma. It is inherited in an autosomal dominant manner and shows high penetrance for diffuse gastric cancer as well as lobular breast cancer. Due to the unreliability of endoscopic detection, the primary management strategy for HDGC is prophylactic total gastrectomy. There is an urgent need for effective drugs for use in conjunction with screening in order to mitigate reliance on surgery.

Germline inactivating mutation of the tumour suppressor gene E-cadherin (CDH1) and its functional relatives accounts for the majority of HDGC diagnoses. E-cadherin is a transmembrane protein that plays key roles in establishing and maintaining cell-cell adhesions, apicobasal polarity and mitosis. Although not amenable to conventional drug targeting, the loss of E-cadherin is predicted to create vulnerabilities that can be targeted.

Synthetic lethal interactions occur between two genes where only inactivation of both genes is lethal, while inactivation of either gene alone is tolerated. Candidate synthetic lethal targets were silenced with shRNA and drugs in an isogenic (CDH1-/- and CDH1+/+) MCF10A background. Quantitation of gene expression and analysis of cell viability following treatment was used to assess synthetic lethal effect.

In this investigation, microtubule-associated targets MAST2 and MAP1B, and mitotic regulators Aurora-A and -B kinase, were identified as vulnerabilities in an E-cadherin-deficient context. Microtubules have been the targets of many drugs since the advent of chemotherapy, and represent a central set of functions that become perturbed in E-cadherin-deficient cells. Given the role of E-cadherin, it is rational to target microtubule and mitotic processes and further investigation of agents that target these functions is warranted.