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Kinase Inhibitor Resistance Mechanisms
As many kinase inhibitors exert their cytotoxic effects primarily by inhibiting a specific kinase, there is a strong selective pressure for cells to acquire resistance through mutations in the kinase gene that abrogate drug binding. Additional non-mutation kinase inhibitor resistance mechanisms have been documented, including target amplification in the case of BCR-ABL1 in CML patients and upregulation of alternative kinase pathways such as hepatocyte growth factor receptor in the acquisition of resistance to EGFR kinase inhibitors that has been observed in lung cancer. Owing to the rapid proliferation of cancer cells, the acquisition of mutations conferring drug resistance has become a recurring theme in the clinic. Indeed, resistance as a result of kinase mutations has been documented for inhibitors of BCR-ABL1 (Supplementary Information S4 , EGFR, FLT3, KIT and PDGFR.To date the most extensive clinical and laboratory characterization of resistance-causing mutations has been performed for BCR-ABL1 in the context of imatinib and second-generation inhibitors. Additionally, it has been shown in several haematological tumours that quiescent stem cells are refractory to tyrosine kinase inhibitors, and these cell populations are probably also involved in resistance mechanisms.
Inhibitor resistance conferred by mutation at the gate-keeper residue — so called because the size of the amino acid side chain at this position determines the relative accessibility of a hydrophobic pocket located adjacent to the ATP binding site (hydrophobic pocket II) — appears to be a common theme for a variety of kinases. Access to this pocket is important to many kinase inhibitors because hydrophobic interactions in this site are crucial for the binding affinity of the inhibitor. For example, the most recalcitrant of the BCR-ABL1 mutants is T315I, which harbours a mutation in the gatekeeper residue. Although the gatekeeper residue often comes in close contact with type 1 and type 2 ATP binding site inhibitors, it typically does not interact with ATP. Consequently, mutation of the gatekeeper residue generally causes little or no change in kinase activity but has the potential to confer inhibitor resistance through a variety of biochemical mechanisms. The T315I gatekeeper mutation in BCR-ABL1 impedes drug binding through loss of a crucial hydrogen bonding interaction to the inhibitor and introduction of a steric clash. Mutation of the EGFR T790 residue to methionine induces resistance to the quinazoline-based inhibitors gefitinib and erlotinib by increasing the affinity for ATP, which effectively weakens the affinity of ATP-competitive inhibitors.
Gatekeeper mutations have been found to confer inhibitor resistance in a number of additional cases. The gatekeeper mutation G697R in FLT3 induces resistance to the type 1 staurosporine derivative PKC412. A systematic investigation of engineered gatekeeper mutations in ABL1, PDGFRβ, SRC and FGFR1 demonstrated that resistance can be achieved against a variety of selective and non-selective inhibitors of these kinases. For example, the T341M mutation of SRC results in resistance to the type I pyrido[2,3-d]pyridinone PP58, mutation of T681I of PDGFRβ confers resistance to both PP58 and imatinib, and the V561M mutation of FGFR1 confers resistance to PP58. There is currently debate as to whether the gatekeeper mutation is pre-existing or acquired following inhibitor treatment. The gatekeeper mutants of BCR-ABL1 (T315I), PDGFRα (T674I), EGFR (T790M) and KIT (T670I) are the most frequently reported mutants for each of these kinases. This suggests that mutation of the gatekeeper amino acid is likely to be a common occurrence in clinical kinase inhibitor resistance and that general methods to design inhibitors that can overcome this mutation would be useful.
Several strategies are being investigated to overcome kinase inhibitor resistance mutants. A first approach is to develop inhibitors that can tolerate diverse amino acids at the gatekeeper position as discussed for T315I BCR-ABL1 inhibitors. A second approach is to target the kinase with inhibitors that bind at alternative binding sites. For example, the ABL1 substrate binding site has been targeted by ON012380, a vinyl sulphone-containing inhibitor, and the myristate binding site has been targeted by the GNF2 class of inhibitors. A third approach involves targeting other pathways that may be required for BCR-ABL1-mediated transformation, such as the chaperone function of HSP90 or farnesyltransferase activity These approaches have been demonstrated to work in cell culture and efforts are currently underway to apply them clinically.
As many kinase inhibitors exert their cytotoxic effects primarily by inhibiting a specific kinase, there is a strong selective pressure for cells to acquire resistance through mutations in the kinase gene that abrogate drug binding. Additional non-mutation kinase inhibitor resistance mechanisms have been documented, including target amplification in the case of BCR-ABL1 in CML patients and upregulation of alternative kinase pathways such as hepatocyte growth factor receptor in the acquisition of resistance to EGFR kinase inhibitors that has been observed in lung cancer. Owing to the rapid proliferation of cancer cells, the acquisition of mutations conferring drug resistance has become a recurring theme in the clinic. Indeed, resistance as a result of kinase mutations has been documented for inhibitors of BCR-ABL1 (Supplementary Information S4 , EGFR, FLT3, KIT and PDGFR.To date the most extensive clinical and laboratory characterization of resistance-causing mutations has been performed for BCR-ABL1 in the context of imatinib and second-generation inhibitors. Additionally, it has been shown in several haematological tumours that quiescent stem cells are refractory to tyrosine kinase inhibitors, and these cell populations are probably also involved in resistance mechanisms.
Inhibitor resistance conferred by mutation at the gate-keeper residue — so called because the size of the amino acid side chain at this position determines the relative accessibility of a hydrophobic pocket located adjacent to the ATP binding site (hydrophobic pocket II) — appears to be a common theme for a variety of kinases. Access to this pocket is important to many kinase inhibitors because hydrophobic interactions in this site are crucial for the binding affinity of the inhibitor. For example, the most recalcitrant of the BCR-ABL1 mutants is T315I, which harbours a mutation in the gatekeeper residue. Although the gatekeeper residue often comes in close contact with type 1 and type 2 ATP binding site inhibitors, it typically does not interact with ATP. Consequently, mutation of the gatekeeper residue generally causes little or no change in kinase activity but has the potential to confer inhibitor resistance through a variety of biochemical mechanisms. The T315I gatekeeper mutation in BCR-ABL1 impedes drug binding through loss of a crucial hydrogen bonding interaction to the inhibitor and introduction of a steric clash. Mutation of the EGFR T790 residue to methionine induces resistance to the quinazoline-based inhibitors gefitinib and erlotinib by increasing the affinity for ATP, which effectively weakens the affinity of ATP-competitive inhibitors.
Gatekeeper mutations have been found to confer inhibitor resistance in a number of additional cases. The gatekeeper mutation G697R in FLT3 induces resistance to the type 1 staurosporine derivative PKC412. A systematic investigation of engineered gatekeeper mutations in ABL1, PDGFRβ, SRC and FGFR1 demonstrated that resistance can be achieved against a variety of selective and non-selective inhibitors of these kinases. For example, the T341M mutation of SRC results in resistance to the type I pyrido[2,3-d]pyridinone PP58, mutation of T681I of PDGFRβ confers resistance to both PP58 and imatinib, and the V561M mutation of FGFR1 confers resistance to PP58. There is currently debate as to whether the gatekeeper mutation is pre-existing or acquired following inhibitor treatment. The gatekeeper mutants of BCR-ABL1 (T315I), PDGFRα (T674I), EGFR (T790M) and KIT (T670I) are the most frequently reported mutants for each of these kinases. This suggests that mutation of the gatekeeper amino acid is likely to be a common occurrence in clinical kinase inhibitor resistance and that general methods to design inhibitors that can overcome this mutation would be useful.
Several strategies are being investigated to overcome kinase inhibitor resistance mutants. A first approach is to develop inhibitors that can tolerate diverse amino acids at the gatekeeper position as discussed for T315I BCR-ABL1 inhibitors. A second approach is to target the kinase with inhibitors that bind at alternative binding sites. For example, the ABL1 substrate binding site has been targeted by ON012380, a vinyl sulphone-containing inhibitor, and the myristate binding site has been targeted by the GNF2 class of inhibitors. A third approach involves targeting other pathways that may be required for BCR-ABL1-mediated transformation, such as the chaperone function of HSP90 or farnesyltransferase activity These approaches have been demonstrated to work in cell culture and efforts are currently underway to apply them clinically.
cancer_inhibition_mechanisms_for_drug_target.pdf | |
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metabolic-mechanisms-of-cancer-induced-inhibition-of-immune-responses.pdf | |
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