During evolution, connections between the major signalling pathways were established to provide cells with an ability to deal with perturbations of homeostasis. However, these feedback and crosstalk mechanisms can become a liability in the treatment of cancer, as the inhibition of one cancer-relevant signalling pathway can lead to the activation of a secondary survival pathway that interferes with cancer drug efficacy. In this review, we discuss connections between signalling pathways in relation to cancer therapy and we evaluate the use of genetic approaches to identify pathway crosstalk. We also discuss how insight into connections between signalling pathways can be exploited to design powerful synthetic lethal drug combination therapies for the treatment of cancer.
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