Response and Resistance to BCR-ABL1-Targeted Therapies

Abstract

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 secondand 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.

Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities

“…Despite sufficient inhibition of BCR-ABL1 protein, many patients can still experience failure of the treatment due to development of BCR-ABL1-independent mechanisms of TKIs resistance. Thus far, these non-mutational mechanisms have been more extensively studied in CML than in Ph+ ALL, and are described in great detail elsewhere [139,148,149]. Alternative activation of the BCR-ABL1 downstream pathways, including JAK/STAT, SRC, MAPK, or PI3K seems to be crucial in mediating this particular resistance phenotype, which explains better efficacy of less selective TKIs [150][151][152].…”

A brief overview of antitumoral actions of bruceine D

“…Chronic myeloid leukemia is a myeloproliferative malignancy that is usually caused by a chromosomal rearrangement event between chromosome 22 and chromosome 9 to form the Philadelphia chromosome [86,87]. It is characterized by over-expression of a fusion oncoprotein BCR-ABL1 that acts as a constitutively active defective tyrosine kinase, implicating downstream signaling pathways such as PI3K/AKT/mTOR, Janus kinase (JAK)/STAT and Ras protein family (Ras)/mitogen-activated protein kinase kinase (MEK), all of which are crucial in maintaining normal cellular proliferation and apoptosis [86,88]. Conventional therapeutic agents like imatinib, nilotinib, dasatinib, ponatinib, and bosutinib, therefore, act as tyrosine kinase inhibitors to prevent constitutive activation of the receptor tyrosine kinases in CML [86,[89][90][91].…”

Clonal Hematopoiesis and Mutations of Myeloproliferative Neoplasms

“…The earliest discovery of genetic aberrations associated with hematological malignancy was the (9;22) translocation or Philadelphia chromosome, resulting in a fusion between the genes coding for BCR and ABL1, identifying patients with chronic myelogenous leukemia (CML). The discovery of tyrosine kinase inhibitor therapies leading to molecular remission of the disease prompted the introduction of molecular assays measuring fusion transcripts to unprecedented sensitivity when monitoring treatment response [1]. The classical Philadelphia chromosome-negative MPNs include essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), which are characterized by driver mutations in a very limited number of phenotypic driver genes: JAK2, CALR, and MPL, involved in activation of the JAK-STAT signaling pathway [2].…”