I13 overrides resistance mediated by the T315I mutation in chronic myeloid leukemia by direct BCR-ABL inhibition

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by a BCR-ABL fusion gene. Imatinib has significantly improved the treatment of CML as a first-generation tyrosine kinase inhibitor (TKIs). The T315I mutant form of BCR-ABL is the most common mutation that confers resistance to imatinib or the second-generation TKIs, resulting in poor clinical prognosis. In this work, we assessed the effect of a potent histone deacetylase (HDAC) inhibitor, I13, on the differentiation blockade in CML cells harboring T315I-mutated and wild-type BCR-ABL by MTT assay, flow cytometery, cell colony formation assay, mRNA Sequencing, Quantitative real-time PCR and Western blotting analysis. We found that I13 possessed highly potent activity against T315I-mutated BCR-ABL mutant-expressing cells and wild-type BCR-ABL-expressing cells. I13 induced cell differentiation and significantly suppressed the proliferation of these CML cells via the cell cycle G0/G1-phase accumulation. Moreover, it was revealed that I13 triggered the differentiation of BaF3-T315I cells, which was attributed to the block of the chronic myeloid leukemia signaling pathway via the depletion of BCR-ABL that was mediated by the inhibition of HDAC activity presented by the acetylation of histones H3 and H4. Taken together, I13 efficiently depleted BCR-ABL in CML cells expressing the BCR-ABL-T315I mutation, which blocked its function, serving as a scaffold protein that modulated the chronic myeloid leukemia signaling pathway mediating cell differentiation. The present findings demonstrate that I13 is a BCR-ABL modulator for the development of CML therapy that can override resistance caused by T315I-mutated BCR-ABL.

Dysregulated Signalling Pathways Driving Anticancer Drug Resistance

“…A T315I point mutation that arises in the BCR-ABL kinase domain is the most frequent mutation in BCR-ABL that causes resistance to first-generation (imatinib) or secondgeneration tyrosine kinase inhibitors (TKIs) that target the BCR-ABL protein, leading to a poor clinical prognosis in chronic myeloid leukaemia [56,57]. Due to the activation of intrinsic signalling pathways, such as the RAS/RAF/MAPK/ERK, GSK3 β and JAK/STAT5 pathways, imatinib intolerance or initial resistance arises, and many leukaemic patients acquire secondary resistance [58][59][60][61].…”

Insights on the Role of Polyphenols in Combating Cancer Drug Resistance

“…Nevertheless, medication resistance due to mutation of the targeted protein may compromise the treatments’ long-term efficacy. Mutations at “gatekeeper” residues, which prevent drugs from entering the kinase back pocket active site, are a common cause of resistance to tyrosine kinase (BCR/ABL and EGFR) inhibitors [ 90 , 91 , 92 ]. Hence, under therapeutic pressure, the most adaptive or resistant heterogeneous subpopulations of cancer cells will be selected.…”

Biological evaluation of combinations of tyrosine kinase inhibitors with Inecalcitol as novel treatments for human chronic myeloid leukemia

“…The effectiveness of Imatinib drug persisted over time with almost 11 years of following up and its long term use showed no unacceptable or late toxic effects ( Hochhaus et al, 2017 ). The most prevalent mutation in BCR-ABL that results in resistance to Imatinib or second-generation TKIs is T315I , which also has a poor clinical prognosis ( Gao et al, 2023 ).

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