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Src kinases as therapeutic targets for cancer

Nature Reviews Clinical Oncology volume 6, pages 587–595 (2009)Cite this article

Abstract

Src family kinases (SFKs) have a critical role in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development. SFKs comprise nine family members that share similar structure and function. Overexpression or high activation of SFKs occurs frequently in tumor tissues and they are central mediators in multiple signaling pathways that are important in oncogenesis. SFKs can interact with tyrosine kinase receptors, such as EGFR and the VEGF receptor. SFKs can affect cell proliferation via the Ras/ERK/MAPK pathway and can regulate gene expression via transcription factors such as STAT molecules. SFKs can also affect cell adhesion and migration via interaction with integrins, actins, GTPase-activating proteins, scaffold proteins, such as p130CAS and paxillin, and kinases such as focal adhesion kinases. Furthermore, SFKs can regulate angiogenesis via gene expression of angiogenic growth factors, such as fibroblast growth factor, VEGF, and interleukin 8. On the basis of these important findings, small-molecule SFK inhibitors have been developed and are undergoing early phase clinical testing. In preclinical studies these agents can suppress tumor growth and metastases. The agents seem to be safe in humans and could add to the therapeutic arsenal against subsets of cancers.

Key Points

  • Src-family kinases (SFKs) are central mediators that involve multiple pathways and can interact with tyrosine kinase receptors, representing a promising target to stop the growth of tumor cells

  • SFKs can regulate gene expression and affect cell adhesion via interaction with integrins, actins, and focal adhesion kinases

  • SFKs consist of nine family members, each composed of four common Src homology domains (SH1, SH2, SH3, SH4) that share similar structures and functions

  • We have a good understanding of how SFKs become activated in human tumors; however, given the multiple functions SFKs regulate, finding the optimal use of SFK inhibitors needs to be further investigated

  • The SFK inhibitors dasatinib, AZD0530, and SKI-606 seem to have promising preclinical activity, and early phase clinical trials of these agents are underway

  • There is a need to identify biomarkers to guide SFK-inhibitor monotherapy and combination therapies using SFK inhibitors

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Figure 1: Structure and activation of c-Src.
Figure 2: SFK signaling pathways and function.
Figure 3: Tumor and stromal cell angiogenesis processes are regulated by SFKs.

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  1. University of South Florida College of Medicine, Tampa, FL, USA

    Lori C. Kim

  2. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Lanxi Song & Eric B. Haura

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E. Haura declares an association with Bristol-Myers Squibb Oncology. The other authors declare no competing interests.

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Kim, L., Song, L. & Haura, E. Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol 6, 587–595 (2009). https://doi.org/10.1038/nrclinonc.2009.129

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