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Cited by 298Cancer Mechanisms and TherapyProtein Kinase Regulation and GTPase SignalingLung Cancer Treatments and Mutations

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Inhibition of Src Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumors

Montero, Juan Carlos, Seoane, Samuel, Ocaña, Alberto, Pandiella, Atanasio·2011·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-10-2616
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Abstract

Dasatinib is a small molecule tyrosine kinase inhibitor that targets a wide variety of tyrosine kinases implicated in the pathophysiology of several neoplasias. Among the most sensitive dasatinib targets are ABL, the SRC family kinases (SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK), and the receptor tyrosine kinases c-KIT, platelet-derived growth factor receptor (PDGFR) α and β, discoidin domain receptor 1 (DDR1), c-FMS, and ephrin receptors. Dasatinib inhibits cell duplication, migration, and invasion, and it triggers apoptosis of tumoral cells. As a consequence, dasatinib reduces tumoral mass and decreases the metastatic dissemination of tumoral cells. Dasatinib also acts on the tumoral microenvironment, which is particularly important in the bone, where dasatinib inhibits osteoclastic activity and favors osteogenesis, exerting a bone-protecting effect. Several preclinical studies have shown that dasatinib potentiates the antitumoral action of various drugs used in the oncology clinic, paving the way for the initiation of clinical trials of dasatinib in combination with standard-of-care treatments for the therapy of various neoplasias. Trials using combinations of dasatinib with ErbB/HER receptor antagonists are being explored in breast, head and neck, and colorectal cancers. In hormone receptor–positive breast cancer, trials using combinations of dasatinib with antihormonal therapies are ongoing. Dasatinib combinations with chemotherapeutic agents are also under development in prostate cancer (dasatinib plus docetaxel), melanoma (dasatinib plus dacarbazine), and colorectal cancer (dasatinib plus oxaliplatin plus capecitabine). Here, we review the preclinical evidence that supports the use of dasatinib in combination for the treatment of solid tumors and describe various clinical trials developed following a preclinical rationale. Clin Cancer Res; 17(17); 5546–52. ©2011 AACR.

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Metadata

Authors
Montero, J. C., Seoane, S., Ocaña, A., & Pandiella, A.
Affiliations
Consejo Superior de Investigaciones Científicas (ES)
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2011-09-01
Volume
17
Issue
17
Pages
5546-5552
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-10-2616
OpenAlex
W2147545245
Cited by
298
References
5
Citations by year
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FWCI
2.75
Type
journal article
Language
en
Open access
closed
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
dasatinib, tyrosine kinase inhibitors, Src family kinases, receptor tyrosine kinase, ABL, CD117, PDGFR, DDR1, c-fms, Eph receptors, combination therapy, solid tumors, breast cancer, prostate cancer, melanoma, colorectal cancer, head and neck cancer, bone microenvironment, osteoclast inhibition, metastasis, apoptosis
MeSH terms
Dasatinib, Antineoplastic Agents, Cell Movement, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms, Pyrimidines, Thiazoles, Biomarkers, Tumor, Apoptosis, src-Family Kinases, Receptor Protein-Tyrosine Kinases, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Tumor Microenvironment

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