Fig. 4. Target structures for pharmacological inhibitors and common escape mechanisms.

a Aberrant activation of tyrosine kinases as a mechanism for malignant transformation. Cancer cells are defined by overactive signalling cascades, often mediated by tyrosine (tyr) kinases. Common therapeutic strategies are either blocking of the tyr kinase receptor by inhibiting antibody/pharmacological inhibitor (which does not work for ligand-independent signals and has reduced potency if the target is overexpressed), or utilising pharmacological inhibitors that block kinase activity (dependent/independent of mutational status). Modified from a previous version³. b Three common escape mechanisms from kinase inhibition. The three common mechanism by which tumour cells escape the blocking effect of small molecule inhibitors are (from left to right): (I) Upregulation of the target structure, for example the tyr kinase receptor. This can occur independently of any genetic alterations and is potentially reversible, i.e., after discontinuation of treatment the tumour can become re-sensitised (as seen, for example, in AML⁸⁹). (II) Mutation of the target structure, so that the inhibitor can no longer bind. This is frequently observed during monotherapy, where only one new selective pressure is applied. For example, initial reports on the novel tyrosine kinase inhibitor imatinib indicated that treatment restored the life expectancy of chronic myelogenous leukaemia patients to that of the general population⁹⁰. While imatinib is a potent drug that greatly improves patients’ quantity and quality of life, treatment-resistant cancer cells frequently emerged and prevented a complete cure⁹¹. (III) Due to the interconnectedness of signalling cascades, inhibition of specific survival molecules can lead to a re-routing or re-wiring of the signals via alternative intermediates, which can result in the formulation of the Nile Distributary hypothesis, that postulates that some cancers are particularly aggressive as they use “multiple cross-covering growth enhancing pathways to grow and avoid cytotoxic interventions”⁹²