Dasatinib: an anti-tumour agent via Src inhibition

Our plain-English summary of Dasatinib: an anti-tumour agent via Src inhibition, by A. Gnoni, I. Marech, N. Silvestris, et al (Current Drug Targets, 2011).

The study

• Authors: A. Gnoni, I. Marech, N. Silvestris, A. Vacca, V. Lorusso
• Journal: Current Drug Targets
• Published: 2011;12(4):563-78
• Type of article: Review
• Cited by: 88 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Dasatinib (BMS-354825, Sprycel®) is an oral, multitargeted inhibitor of receptor tyrosine kinases (RTKs), including BCR-ABL fusion protein, stem cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGFR), and Src family kinases (SFKs). Several early- and late-phase clinical trials for chronic myelogeneous leukaemia (CML) have demonstrated the direct inhibition of BCR-ABL fusion protein and SFKs, which led to dasatinib approval by the Food and Drug Administration (FDA) and the European Union for the treatment of imatinib-resistant or -intolerant CML, and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Phase III dose-optimization study was performed to compare different regimens, stating that dasatinib 100 mg once daily is now the recommended schedule for patients with chronic CML, and 140 mg once daily for patients with accelerated phase or myeloid or lymphoid blast phase CML, and for patients with Ph+ ALL until progression. Because of the myriad of critical roles of SFKs in biological processes, SFKs inhibition could induce numerous biological responses. Ongoing clinical trials evaluate dasatinib in the treatment of several solid tumours, including gastrointestinal stromal tumours (GIST), prostate cancer, malignant pleural mesothelioma, sarcomas, NSCLC, colorectal cancer, glioblastoma and other haematologic malignancies as multiple myeloma. Ongoing pre-clinical studies assess the therapeutic potential of dasatinib in other solid tumours, including melanoma, head and neck cancer, breast cancer and ovarian cancer. Dasatinib is generally well tolerated. Myelosuppression is the common adverse event which is, however, reversible by dose reduction, discontinuation, or interruption. Thrombocytopenia is more significant than neutropenia and associated to gastrointestinal bleeding and CNS haemorrhage. The most common non-haematologic adverse events include gastrointestinal symptoms (diarrhoea, nausea, vomiting, abdominal pain and anorexia), headache, peripheral edema, and pleural effusion. In respect of these encouraging studies investigating dasatinib in the treatment of patients with GIST, prostate cancer, multiple myeloma and sarcomas, ongoing phase III clinical trials warrant the drug evaluation as recommended agent for the treatment of these diseases, also in association with chemotherapy or other targeted therapies.

In plain English

This article is a review, not an original study. The authors summarized published laboratory and clinical research on dasatinib, an oral cancer drug that blocks Src family kinases and other enzymes, including BCR-ABL. A substantial early section covers chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia, including trials that led to approval for patients resistant to or intolerant of imatinib or other prior therapy. It also describes side effects, including low blood counts and fluid build-up such as pleural effusion, and research in several solid tumours. A short section covers malignant pleural mesothelioma. The authors reported that, in laboratory work they cited, dasatinib led to cell cycle arrest, cell death and less migration and invasion in mesothelioma cell lines. They also reported that c-Src expression was common in mesothelioma tissue and that its activation correlated with advanced stage. An early-phase trial in patients with resectable pleural mesothelioma was described as ongoing. No results in mesothelioma patients were given. The article does not discuss asbestos. The authors concluded that dasatinib appears safe and promising for metastatic solid tumours that did not respond to standard therapies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published preclinical and clinical studies of the drug dasatinib (not an original study)
• Who was studied: No population of its own. The reviewed studies covered patients and cell lines in chronic myeloid leukaemia, Philadelphia chromosome-positive acute lymphoblastic leukaemia and several solid tumours. These included malignant pleural mesothelioma: cell lines, tumour tissues, and an ongoing trial in resectable disease at M.D. Anderson Cancer Center
• Exposure: Treatment with dasatinib, an oral kinase inhibitor drug. No asbestos or other fiber exposure is studied or discussed. In the ongoing mesothelioma trial the dose was 70 mg twice daily for 28 days, for up to 2 years after surgery
• Main results:
  • Reviewed mesothelioma laboratory research: inhibiting Src family kinases with dasatinib led to cell cycle arrest, apoptosis, and inhibition of migration and invasion in malignant pleural mesothelioma cell lines
  • Reviewed mesothelioma tissue findings: c-Src expression was common in malignant pleural mesothelioma tissues, and its activation correlated with advanced stage
  • Reported approval: in June 2006 the FDA approved dasatinib for chronic, accelerated or blastic phase CML resistant or intolerant to imatinib. It also approved the drug for Ph+ acute lymphoid leukaemia resistant or intolerant to prior therapy
  • Reviewed START-R trial in chronic-phase CML patients after imatinib failure: complete haematologic response was 93% with dasatinib vs 82% with high-dose imatinib (p=0.034)
  • Reviewed Phase III dose-optimization trial in 670 chronic-phase CML patients: lower rates of pleural effusion (all grades) were reported, 7% vs 16% (P = 0.024)
  • Reviewed toxicity data: in patients with thrombocytopenia, the associated rates of gastrointestinal bleeding and CNS haemorrhage were 4% and 1%
  • Reviewed Phase II trial in metastatic castration-resistant prostate cancer: the composite response or stable disease rate was achieved in 13 of 47 patients (28%)
• The authors' conclusion: The authors concluded that dasatinib is effective for patients with CML. They also concluded that it appears safe and a promising agent for metastatic solid tumours refractory to standard therapies
• Limitations the authors state:
  • The authors stated that observation of a larger series of patients is required to confirm dasatinib resistance

Topics

Medical terms in this study, explained in our Lexicon: STEM, Platelet-Derived Growth Factor (PDGF), Clinical Trial, Pleural Mesothelioma, Sarcoma, Colorectal Cancer, Myeloma, Ovarian Cancer.

Related studies

• Phase II study of dasatinib in patients with previously treated malignant mesothelioma (cancer and leukemia group B 30601): a brief report — A.Z. Dudek, H. Pang, et al. (2012)
• Single-center study to determine the safety and efficacy of CT-707 in Chinese patients with advanced anaplastic lymphoma kinase-rearranged non-small-cell lung cancer — P. Song, X. Zhang, et al. (2020)
• Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors — N. Echeverry, G. Ziltener, et al. (2015)
• Deficiency of Fyn protein is prerequisite for apoptosis induced by Src family kinase inhibitors in human mesothelioma cells — R. Eguchi, S. Kubo, et al. (2012)
• Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma — P. Indovina, E. Marcelli, et al. (2014)
• Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy — K. Schelch, M.A. Hoda, et al. (2014)

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