ReviewKeynoteExploiting receptor tyrosine kinase co-activation for cancer therapy

•Description of the key general principles of RTK co-activation in cancer.•Hierarchical RTK networks maintain robust signalling and drive drug resistance.•Computational methods can interrogate RTK dependencies using high-throughput data.•Future advances could yield therapies to target RTK co-activation in multiple cancers.

Studies over the past decade have shown that many cancers have evolved receptor tyrosine kinase (RTK) co-activation as a mechanism to drive tumour progression and limit the lethal effects of therapy. This review summarises the general principles of RTK co-activation and discusses approaches to exploit this phenomenon in cancer therapy and drug discovery. Computational strategies to predict kinase co-dependencies by integrating drug screening data and kinase inhibitor selectivity profiles will also be described. We offer a perspective on the implications of RTK co-activation on tumour heterogeneity and cancer evolution and conclude by surveying emerging computational and experimental approaches that will provide insights into RTK co-activation biology and deliver new developments in effective cancer therapies.