The landscape of BCR‐ABL mutations in patients with Philadelphia chromosome‐positive leukaemias in the era of second‐generation tyrosine kinase inhibitors

Abstract

BCR-ABL mutations are associated with resistance to tyrosine kinase inhibitors (TKIs) in Philadelphia chromosome-positive leukaemia. The emergence of these mutations in the era of second-generation TKIs, such as dasatinib and nilotinib, remains an evolving field. We conducted a retrospective study to quantitatively characterize the BCR-ABL transcript and mutation status during treatment with first-generation and second-generation TKI therapies. BCR-ABL mutations were detected by direct sequencing for patients with Philadelphia chromosome-positive leukaemia receiving TKI therapies. The efficacy of TKI therapy was quantitatively assessed by calculating the log reduction of BCR-ABL transcripts, which was measured using real-time quantitative polymerase chain reaction. Fisher's exact test was performed to analyse the associations of log reduction <3 and mutation status. We found 35 patients harbouring 55 mutations of 43 different types, of which 30% occurred in patients receiving imatinib, 27% in nilotinib, and 43% in dasatinib. We found a novel germline mutation, N336 N (AACàAAT), and two novel frameshift mutations, Asn358Thr fs*14 and Gly251Ala fs*16. T315I was the most common missense mutation, followed by V299L and F317L. Intron 8 35-bp insertion was the most frequent frameshift mutation. Both missense and multiple BCR-ABL mutations were significantly associated with worse molecular response compared with the molecular response of patients without mutation. Missense mutations, rather than frameshift, were associated with less log reduction, while the T315I, F317L, and T315A mutations were significantly correlated with poor log reduction. Collectively, amino acid

Dysregulated Signalling Pathways Driving Anticancer Drug Resistance

“…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]. Most cellular intrinsic mechanisms play a role in the development of resistance, either directly through BCR-ABL1 point mutations, which predominate in primary resistance, or indirectly through the activation of signalling pathways independent of BCR-ABL1, which frequently lead to disease recurrence and therapy relapse [59,62]. Typically, such activation frequently occurs in a BCR-ABL1-independent manner; as a result, those oncogenic pathways continue to be active even after treating leukaemic cells with imatinib, including nonmutated BCR-ABL1 cells.…”

Targeting integrated stress response with ISRIB combined with imatinib treatment attenuates RAS/RAF/MAPK and STAT5 signaling and eradicates chronic myeloid leukemia cells

“…Many patients show primary or secondary resistance to imatinib or second-generation tyrosine kinase inhibitors (TKIs), such as dasatinib, nilotinib and bosutinib. The resistance originates in the majority of cellular intrinsic mechanisms, either mediated directly by BCR-ABL1 point mutations, which are predominant in primary resistance, or by activation of BCR-ABL1-independent signaling pathways, often responsible for recurrence of the disease and therapy relapse [ 6 , 7 ]. The most recognized pathways responsible for resistance include JAK2/STAT5, RAS/RAF/MAPK and PI3K/Akt/mTOR [ 5 , 8 , 9 ].…”

Targeting Integrated Stress Response by ISRIB combined with imatinib attenuates STAT5 signaling and eradicates therapy-resistant Chronic Myeloid Leukemia cells

“…Apart from BCR-ABL1 point mutations (e.g. T315I) which affect drug binding affinity 6,7 , the BCR-ABL1 gene amplification or clonal evolution may lead to relapse driven by both BCR-ABL1-dependent and -independent mechanisms.…”