Chronic myeloid leukemia: the paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy

Abstract

Deregulated activity of BCR-ABL1, a nonreceptor tyrosine kinase encoded by the fusion gene resulting from the t(9;22)(q34;q11) chromosomal translocation, is thought to be the driver event responsible for initiation and maintenance of chronic myeloid leukemia (CML). BCR-ABL1 was one of the first tyrosine kinases to be implicated in a human malignancy and the first to be successfully targeted. Imatinib mesylate, the first tyrosine kinase inhibitor (TKI) to be approved for therapeutic use, was hailed as a magic bullet against cancer and remains one of the safest and most effective anticancer agents ever developed. Second- and third-generation TKIs were later introduced to prevent or counteract the problem of drug resistance, that may arise in a small proportion of patients. They are more potent molecules, but have been associated to more serious side effects and complications. Patients achieving stable optimal responses to TKI therapy are predicted to have the same life expectancy of the general population. However, TKIs do not ‘cure’ CML. Only a small proportion of cases may attempt therapy discontinuation without experiencing subsequent relapse. The great majority of patients will have to assume TKIs indefinitely – which raises serious pharmacoeconomic concerns and is now shifting the focus from efficacy to compliance and quality of life issues. Here we retrace the steps that have led from the biological acquisitions regarding BCR-ABL1 structure and function to the development of inhibitory strategies and we discuss drug resistance mechanism and how they can be addressed.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0780-6) contains supplementary material, which is available to authorized users.

The Network of Non-coding RNAs in Cancer Drug Resistance

“…Imatinib was approved for clinical treatment of CML but the problem of drug resistance encouraged the development of new TKI generations (440). Various ncRNAs have been associated with imatinib in CML, either as enhancers or inhibitors.…”

Early molecular response ≤1% has strong prognostic impact for CML patients that switch to second‐line therapy with BCR‐ABL1 ≤10% and no major molecular response

“…Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm characterized by an acquired balanced chromosomal translocation with a constitutively active tyrosine kinase ( BCR‐ABL1 ) (Soverini et al , ). The introduction of imatinib mesylate (IM), the first tyrosine kinase inhibitor (TKI) that specifically targeted BCR‐ABL1 oncoprotein, significantly increased survival and quality of life, particularly for those patients in chronic phase (Druker et al , ).…”

Genetic alterations of KIT during clonal expansion and subsequent acquisition of resistance to toceranib in a canine mast cell tumor cell line

“…The TKI resistance mechanism in tyrosine kinase mutation‐driven tumors has been intensively investigated in human tumors, with examples including imatinib resistance in KIT mutation‐driven gastrointestinal stromal tumor (GIST) (Wang et al, ), imatinib resistance in BCR‐ABL mutation‐driven chronic myelogenous leukemia (CML) (Soverini, Mancini, Bavaro, Cavo, & Martinelli, ), and gefitinib/erlotinib resistance in epidermal growth factor receptor (EGFR) mutation‐driven lung cancer (Nagano, Tachihara, & Nishimura, ). One of the major mechanisms underlying acquired resistance to TKIs in these tumors is accumulation of additional mutations (secondary mutations) accompanied by concomitant reactivation of the tyrosine kinase, even in the presence of the TKI (Nagano et al, ; Soverini et al, ; Wang et al, ).…”