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Dasatinib is an anticancer drug thattargets various types of cancer by binding to and inhibiting specific protein kinases involved in cancer cell growth and progression. Since its approval by regulatory agencies, Dasatinib has revolutionized the treatment of certain cancers and provided hope to thousands of patients. This article explores the science behind Dasatinib drugs and their clinical applications.
Mechanism of Action
Dasatinib works by inhibiting the activity of tyrosine kinases, a class of enzymes that play important roles in signal transduction pathways. In particular, Dasatinib potently inhibits BCR-ABL, which is a constitutively active tyrosine kinase due to the Philadelphia chromosome translocation found in chronic myeloid leukemia (CML). By blocking BCR-ABL, Dasatinib prevents the abnormal signals that promote uncontrolled division of CML cells. Dasatinib also inhibits several other tyrosine kinases that have been implicated in different cancers including SRC family kinases, c-Kit, PDGFRs, and Ephrin A2 receptor. This multi-targeted inhibition enables Dasatinib drugs to be used against various cancer types beyond just CML.
Clinical Use in CML
The first FDA approval of Dasatinib was in 2006 for the treatment of adults with CML in either newly diagnosed chronic phase or with resistance or intolerance to prior therapy including imatinib (Gleevec). Numerous clinical trials have established Dasatinib as a highly effective treatment option for CML. In one large trial, over 70% of newly diagnosed chronic phase CML patients achieved a complete cytogenetic response within 12 months of starting Dasatinib. It also induced responses in a high proportion of patients who failed on prior tyrosine kinase inhibitor therapy like imatinib. Dasatinib is generally well-tolerated with the most common side effects being mild like nausea and diarrhea. Due to its favorable safety and superior efficacy profiles compared to other TKIs, Dasatinib is now widely used as the standard first-line treatment for chronic phase CML.
Activity Against Other Cancers
In addition to CML, Dasatinib has demonstrated clinical activity against other types of cancer driven by its molecular targets. It received subsequent FDA approvals for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in 2010 and for adults with multiple types of cancer in 2014. Some of the other cancers where Dasatinib has shown therapeutic benefits either as monotherapy or in combinations include non-small cell lung cancer driven by EGFR mutations, melanoma harboring KIT mutations, and tumors originating from the gastrointestinal stromal. Ongoing research continues to reveal new cancer types that may be amenable to Dasatinib treatment.
Combination Therapies
While Dasatinib can induce remissions as monotherapy in certain cancers, combining it with other anti-cancer drugs often results in improved outcomes. For instance, in Ph+ ALL the standard first-line regimen contains Dasatinib along with chemotherapy. Similarly, Dasatinib improves the efficacy of chemotherapy when used before or after hematopoietic stem cell transplant in CML patients who relapse post-transplant. Preclinical studies also suggest that Dasatinib can synergize with immunotherapy agents like PD-1/PD-L1 inhibitors. Several combination strategies of Dasatinib with immunotherapies, chemotherapy or other targeted drugs are currently under evaluation in clinical trials against various solid and hematological malignancies.
Overcoming Resistance
Like other targeted therapies, resistance can diminish the long-term efficacy of Dasatinib if used as monotherapy. The main mechanisms of acquired resistance to Dasatinib involve mutations that interfere with its binding to target kinases or mutations in downstream signaling pathways. Second generation TKIs capable of overriding some of the common Dasatinib-resistance mutations have been developed. Switching to one of these second-generation inhibitors upon relapse usually restores response. Recently, a drug named ponatinib that retains activity against virtually all known BCR-ABL mutations has shown impressive long-term results in highly treatment-refractory CML and Ph+ ALL in clinical trials, representing a major step forward.
Conclusions
Since its approval 15 years ago, Dasatinib has become an indispensable part of the modern therapies against multiple leukemias and solid tumors. Continuous research efforts now allow optimizing its use through rational combinations and sequential regimens. With the addition of second generation TKIs and novel combination strategies currently in clinical testing, targeted therapy with Dasatinib and related drugs promises even brighter long-term outcomes for cancer patients in the future.
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- Source: Coherent Market Insights, Public sources, Desk research
- We have leveraged AI tools to mine information and compile it
