TY - JOUR
T1 - Response and Resistance to BCR-ABL1-Targeted Therapies
AU - Braun, Theodore P.
AU - Eide, Christopher A.
AU - Druker, Brian J.
N1 - Funding Information:
Funding provided by KL2TR002370-03 to T.P.B. Howard Hughes Medical Institute and R01 CA065823-24 to B.J.D. B.J.D. potential competing interests––SAB: Aileron Therapeutics, Therapy Architects (ALLCRON), Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, EnLiven Therapeutics, Gilead Sciences (inactive), Monojul (inactive); SAB & Stock: Aptose Biosciences, Blueprint Medicines, Iterion Therapeutics, Third Coast Therapeutics, GRAIL (SAB inactive); Scientific Founder: MolecularMD (inactive, acquired by ICON); Board of Directors & Stock: Amgen; Board of Directors: Burroughs Wellcome Fund, CureOne; Joint Steering Committee: Beat AML LLS; Founder: VB Therapeutics; Clinical Trial Funding: Novartis, Bristol-Myers Squibb, Pfizer; Royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana-Farber Cancer Institute (one Merck exclusive license). The remaining authors have no competing interests to declare.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/4/13
Y1 - 2020/4/13
N2 - Chronic myeloid leukemia (CML), caused by constitutively active BCR-ABL1 fusion tyrosine kinase, has served as a paradigm for successful application of molecularly targeted cancer therapy. The development of the tyrosine kinase inhibitor (TKI) imatinib allows patients with CML to experience near-normal life expectancy. Specific point mutations that decrease drug binding affinity can produce TKI resistance, and second- and third-generation TKIs largely mitigate this problem. Some patients develop TKI resistance without known resistance mutations, with significant heterogeneity in the underlying mechanism, but this is relatively uncommon, with the majority of patients with chronic phase CML achieving long-term disease control. In contrast, responses to TKI treatment are short lived in advanced phases of the disease or in BCR-ABL1-positive acute lymphoblastic leukemia, with relapse driven by both BCR-ABL1 kinase-dependent and -independent mechanisms. Additionally, the frontline CML treatment with second-generation TKIs produces deeper molecular responses, driving disease burden below the detection limit for a greater number of patients. For patients with deep molecular responses, up to half have been able to discontinue therapy. Current efforts are focused on identifying therapeutic strategies to drive deeper molecular responses, enabling more patients to attempt TKI discontinuation.
AB - Chronic myeloid leukemia (CML), caused by constitutively active BCR-ABL1 fusion tyrosine kinase, has served as a paradigm for successful application of molecularly targeted cancer therapy. The development of the tyrosine kinase inhibitor (TKI) imatinib allows patients with CML to experience near-normal life expectancy. Specific point mutations that decrease drug binding affinity can produce TKI resistance, and second- and third-generation TKIs largely mitigate this problem. Some patients develop TKI resistance without known resistance mutations, with significant heterogeneity in the underlying mechanism, but this is relatively uncommon, with the majority of patients with chronic phase CML achieving long-term disease control. In contrast, responses to TKI treatment are short lived in advanced phases of the disease or in BCR-ABL1-positive acute lymphoblastic leukemia, with relapse driven by both BCR-ABL1 kinase-dependent and -independent mechanisms. Additionally, the frontline CML treatment with second-generation TKIs produces deeper molecular responses, driving disease burden below the detection limit for a greater number of patients. For patients with deep molecular responses, up to half have been able to discontinue therapy. Current efforts are focused on identifying therapeutic strategies to drive deeper molecular responses, enabling more patients to attempt TKI discontinuation.
KW - BCR-ABL
KW - CML
KW - targeted therapy
KW - tyrosine kinase inhibitor
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U2 - 10.1016/j.ccell.2020.03.006
DO - 10.1016/j.ccell.2020.03.006
M3 - Review article
C2 - 32289275
AN - SCOPUS:85082765072
VL - 37
SP - 530
EP - 542
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 4
ER -