Editors' ChoiceCancer

A (synthetic) lethal weapon for cancer

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Science Translational Medicine  18 Apr 2018:
Vol. 10, Issue 437, eaat4477
DOI: 10.1126/scitranslmed.aat4477

Abstract

ROS1 inhibition in E-cadherin–deficient tumors leads to synthetic lethality, which could be exploited for the selective treatment of breast cancer patients.

Synthetic lethality occurs between two genes when the alteration of either gene alone enables cell viability but the simultaneous perturbation of both genes leads to cell death. The concept of synthetic lethality is highly interesting for cancer therapy as it predicts that a drug that inhibits the protein product of the first gene will induce the death of cancer cells harboring an inactivating mutation of the second gene. Cancer therapies that exploit synthetic lethality are also expected to have reduced toxicity since only the cancer cells—and not the normal cells—present the cancer-specific mutation that confers sensitivity to the drug treatment. In a recent study, Bajrami et al. identify a novel synthetic lethal interaction between E-cadherin, a gene that is frequently mutated in breast cancer, and ROS1, a gene whose protein product can be inhibited by approved drugs, a finding that can potentially be rapidly translated into the clinics.

E-cadherin is a cell adhesion protein whose expression is lost in a high percentage of breast cancer patients. By performing chemical and genetic screens in E-cadherin–isogenic breast cancer cells, the authors established ROS1 inhibition as synthetic lethal with E-cadherin deficiency. This finding that ROS1 inhibition, either genetically or with small-molecule inhibitors, affects E-cadherin–deficient cells was subsequently validated in in vitro experiments, as well as in ex vivo and in vivo models. Mechanistically, ROS1 inhibition induced mitosis abnormalities that were exacerbated by E-cadherin deficiency, which contributed to aberrant cytokinesis, increased DNA damage, and cell death.

This finding could represent a breakthrough for 13% of breast cancer patients and 90% of lobular breast cancer patients that harbor E-cadherin inactivation. Furthermore, it could potentially be translated to other tumor types, such as gastric cancer, that frequently present E-cadherin deficiency. A clinical trial testing crizotinib, a ROS1 inhibitor already approved for the treatment of non–small cell lung cancer, in E-cadherin–deficient lobular breast cancer patients is ongoing. If successful, this will represent the second example of breast cancer therapy based on the concept of synthetic lethality, following the seminal treatment of BRCA1-deficient patients with PARP inhibitors.

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