Targeting the cancer kinome through polypharmacology

Abstract

Kinase inhibitors are the largest class of new cancer drugs. However, it is already apparent that most tumours can escape from the inhibition of any single kinase. If it is necessary to inhibit multiple kinases, how do we choose which ones? In this Opinion article, we discuss some of the strategies that are currently being used to identify new therapeutic combinations of kinase targets.

Figure 1. Resistance to kinase inhibitors

a | Mechanisms of acquired resistance. treatment with kinase inhibitors can select for mutations that block drug binding (left panel). this was first demonstrated for the T315I mutation in BCR–ABL in chronic myeloid leukaemia. treatment with a kinase inhibitor can induce upregulation of a second kinase that substitutes for the drug target (centre panel). The receptor tyrosine kinase MET (also known as hepatocyte growth factor receptor) has been shown to be overexpressed in lung cancer cells that acquire resistance to epidermal growth factor receptor (EGFR) inhibitors. Tumour cells can respond to treatment with a kinase inhibitor by down-regulating the phosphatase that normally dephosphorylates the substrates of that kinase (right panel). This has the effect of decreasing the cellular potency of the kinase inhibitor. this mechanism has been observed in acquired resistance to EGFR inhibitors in breast cancer cells. b | Mechanisms of intrinsic resistance. Many tumours express multiple oncogenic kinases that signal redundantly to promote cell survival (left panel). For example, some gliomas show constitutive activation of multiple receptor tyrosine kinases. Mutational activation of a downstream pathway component can reduce the effectiveness of a kinase inhibitor (right panel). KRAS mutations are associated with resistance to EGFR inhibitors in lung and colorectal cancer–. IGF1R, insulin-like growth factor 1 receptor; INSR, insulin receptor; P, phosphorylation.

Figure 2. Degrees of oncogene addiction

Three examples of oncogene addiction drawn from the recent literature. a | Treatment of K252a chronic myeloid leukaemia (CML) cells with the BCR–ABL inhibitor imatinib results in complete cell death by day 4 (REF. 31). b | Disruption of the KRAS^G13D oncogene in DLD-1 colorectal cancer cells slows the rate of cell proliferation. c | Disruption of the PIK3CA^H1047R oncogene in HCT-116 colorectal cancer cells slows the rate of cell proliferation. WT, wild type.

Figure 3. Strategies for multi-targeted kinase inhibition

a | The single agent PP121 was shown to target both tyrosine kinases (such as vascular endothelial growth factor receptor 2, BCR–ABL and RET) and PI3K family members such as PIK3CA and mTOR (inhibitor targets are shown in red boxes). Note that the combined inhibition of mTOR and PI3K by PP121 disables a negative feedback loop in which mTOR inhibits PI3K. b | the combination of the MEK inhibitor AZD6244 and the Akt inhibitor MK-2206 results in the inhibition of both the MAPK and PI3K pathways. This combination is being evaluated in clinical trials. RTK, receptor tyrosine kinase.

Figure 4. Selectivity profiling of kinase inhibitors

a | The number of kinases available for screening from commercial vendors by year. the complete human kinome includes approximately 520 protein kinases and a smaller number of lipid and small molecule kinases. b | Landmark papers in kinase inhibitor selectivity profiling–,,,, plotted against the number of selectivity measurements (kinases × drugs) that were reported. Representatives from three different approaches that measure inhibitor binding are shown.

Figure 5. Polypharmacology in the protein kinome

Pairs of kinases were associated based on kinase selectivity data for a broad range of inhibitor scaffolds and the sequence conservation between aligned sequences of an expanded ATP binding site. Pairs of kinases that were potently inhibited by a common inhibitor (common dissociation constant (K_D)<10 nM) (green lines) were used to determine a sequence similarity cut-off to predict pairs of kinases that can be inhibited by a common inhibitor (red lines). A much higher sequence similarity in the binding pockets was observed for those pairs of kinases with a common potent inhibitor compared with pairs of kinases with a common but less potent inhibitor or no common inhibitor at all. The level of sequence conservation necessary for the predictions was determined based on the sequence conservation distribution of the experimentally determined pairs. The predicted pairs of kinases (red lines) represent potential target combinations that may be more easily accessible with new kinase inhibitors. The image is shown in more detail in supplementary information s1 (figure). AGC, kinases from the protein kinase A, protein kinase G and protein kinase C families; CAMK, calcium/calmodulin-dependent protein kinases; CK1, casein kinase 1; CMGC, kinases from the cyclin-dependent kinase, MAP kinase, glycogen synthase kinase and casein kinase II families; STE, homologues of yeast sterile 7, sterile 11 and sterile 20 kinases; TK, tyrosine kinases; TKL, tyrosine kinase-like kinases.