Kinase Mutations and Resistance in Cancer

World Wide Medicinal Chemistry, Pfizer Global Research and Development, 445 Eastern Point Road, Groton CT 06340, United States of America 

RSC Drug Discovery Series No. 19 Kinase Drug Discovery 

Edited by Richard A. Ward and Frederick Goldberg Royal Society of Chemistry 2012 

Several inactive states of the kinase have been identified and been characterized by protein crystallography and NMR studies (See Table 5.1 for a listing of crystal structures of marketed kinase inhibitors). One important class of inactive conformation is the DFG-out , in which the activation loop partly occludes the ATP site, with the Asp and Phe residues pointed away from the ATP site.4 This has been extremely important to drug discovery efforts as a 

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Wang SE, Narasanna A, Perez-Torres M et al. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 2006 10 25-38. 

Shah, N. P., Nicoll, J., Nagar, B., et al. (2002) Multiple BRC-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (ST1571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2, 117-125. 

It is difficult to deconvolute how kinase inhibitor binding mode has implications in the clinic. In general, selectivity tends to increase in the order (i) purine site, (ii) selectivity pocket, and (iii) allosteric site. The ability to overcome resistance mutations in cancer therapy tends to be inversely related to this selectivity pattern. Accordingly, allosteric kinase inhibition may become a preferred mechanism for clinical indications other than cancer. 

Figure 5.6 The Her2-dependent survival pathway is activated in many EGF-dependent breast cancers. Suppression of Her-2 by the binding of trastuzumab normally decreases PI3K kinase activation of AKT, and therefore reduces the downstream cell survival signal. Activating mutations of PI3K kinase (e.g. by reducing the binding of the P85 regulatory unit) or suppression of PTEN expression both increase AKT signaling and therefore cell survival. Both are implicated in trastuzumab resistance in the clinic.

Given the convergence between the resistance mutations found in cancer and the mutations used to engineer orthogonal kinase ligands, it is reasonable... 

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