Similar results had been seen with QLT0267, an integrin signaling inhibitor 115

Comparable final results were observed with QLT0267, an integrin signaling inhibitor.115 Drug Combinations & Synthetic Lethality Although stem cells express, but are not addicted to, BCR-ABL it may still be possible to manipulate other pathways which assume an essential role in response to ABL inhibition. This idea of synthetic lethality for cancer therapy is not new, but has recently received more attention in the CML field propelled by emerging data demonstrating BCR-ABL independent disease persistence on TKI therapy. In an RNAi-based screen for dysregulated genes in response to imiatinib therapy, the Wnt pathway emerged as the viable target for a second hit.116 Other critical Selumetinib kinase inhibitor pathways involved in disease progression inhibitor chemical structure or leukemic cell function have become attractive targets to augment BCR-ABL inhibition. For example, inhibition of ATG7,117 MUC1,118 Alox5,119 and mTOR120 have all been investigated in pre-clinical studies because they do not cause loss of hematopoetic stem cell function, but instead target the leukemic clone in combination with TKIs. A list of recent clinical trials for combination therapies can be found in table 2. Finally, transcription factors such as STAT5 can mediate resistance to TKIs.121 Some patients in BC-CML have significant downregulation of STAT-inhibitor proteins, potentiating cell survival and residual disease.
122 A new STAT5 inhibitor, pimozide, is able to decrease STAT5 and its target genes, resulting in growth inhibition of Ph+ patient samples independently of ABL mutations.123 The precise mechanism of action of this compound is not known. For a comprehensive discussion on other signal transduction pathways in CML, the reader is refered to the referenced chapter.
124 Conclusions The rational design of drugs targeting BCR-ABL has made CML a manageable disease, reversible PARP inhibitor selleck resulting in prolonged survival for most patients. Mutations resulting in resistance to imatinib have driven development of the second-generation TKIs nilotinib and dasatinib. These inhibitors are active against a broad spectrum of BCR-ABL mutants, with the notable exception of the T315I ‘gatekeeper’ mutant, which in turn has led to third-generation inhibitors. The most advanced of these is ponatinib, which has been termed a ‘pan-BCRABL inhibitor’, as it does not have identifiable gaps in BCR-ABL coverage. As complete ablation of BCR-ABL activity becomes a reality, the question arises whether we will see BCR-ABL-independent resistance emerge as a unifying feature of TKI failure. As the field has focused on the role of kinase domain mutations, relatively little is known about these mechanisms. On the other side of the response spectrum is minimal residual leukemia despite prolonged TKI therapy.

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