The application value of bosutinib/bosutinib in blast crisis CML

Bosutinib/Bosutinib (Bosutinib) is an oral tyrosine kinase inhibitor (TKI), mainly used to treat chronic myelogenous leukemia (CML), especially in patients who are resistant or intolerant to first-line treatment, showing good efficacy. Its mechanism of action not only targets the Bcr-Abl fusion protein, but also significantly inhibits Src family kinases (SFKs), which makes bosutinib a potential advantage in the treatment of CML patients in the progressive phase, especially the blast phase. Blast phase CML is the most difficult to treat clinically. It usually manifests as an acute leukemia-like course with extremely poor prognosis. Traditional treatment methods have low response rates and strong drug resistance. Therefore, there is an increasingly urgent need for more potent targeted drugs with more comprehensive mechanisms of action.

At the molecular level,Src family kinases are widely involved in cell signal transduction pathways and regulate cell proliferation, migration, invasion and survival mechanisms. During the blast phase of CML, these kinases are often abnormally activated, leading to highly malignant leukemia cells, resistance to conventional treatments, and further collapse of the hematopoietic system. Bosutinib's high-affinity inhibition of Src kinase can block this abnormal signaling to a certain extent, thereby reducing the expansion ability of leukemia cells and possibly reversing certain drug resistance mechanisms. This feature makes its potential role in the treatment of blast phase CML far greater than that of traditional first-generation TKIs that only target Bcr-Abl, such as imatinib.

Compared with otherTKIs, bosutinib has a broader spectrum of kinase inhibitory properties. Although its targeting potency against Bcr-Abl is slightly lower than that of nilotinib or dasatinib, its synergistic inhibitory effect on Src kinase may make it more effective in blast crisis patients with complex drug-resistant mutations or highly heterogeneous disease. For example, some Bcr-Abl mutations (such as F317L) have been proven to be resistant to first- or second-generation TKIs, and bosutinib has certain sensitivity to these mutations in clinical studies and may provide new treatment options for patients who have failed multiple lines of treatment.

In actual treatment, the response rate and overall survival of CML in the blast phase are affected by many factors, including mutation spectrum, bone marrow status, previous treatment history, and comorbidities. Bosutinib, as a single agent or part of combination therapy, is being explored in an increasing number of clinical trials for its efficacy in blast crisis. Some current international studies have shown that bosutinib can achieve hematological remission and partial cytogenetic remission in blast phase CML patients. Especially after those first-line or second-line TKI treatments are ineffective, bosutinib has shown certain efficacy and tolerability as a third-line or fourth-line regimen. It is worth noting that its side effect spectrum includes gastrointestinal reactions, liver function abnormalities and hematological toxicity, but it is within a controllable range, especially on the basis of individualized dose management, which can significantly improve patient tolerance.

With the in-depth research on targeted therapy, more and more evidence shows that multi-target inhibition strategy may be the key to solvingTKI resistance problem. The Src kinase-mediated signaling pathway not only exists in CML, but also plays an important role in other solid tumors such as breast cancer and lung cancer. Therefore, from the perspective of molecular targets, the development and application of bosutinib also has the potential to expand into a variety of refractory tumors. At the same time, its combination with comprehensive treatments such as immunotherapy and hematopoietic stem cell transplantation also provides more possibilities for personalized treatment in the future.

Reference materials:https://go.drugbank.com/drugs/DB06616