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. 2011 Dec 1;1(12):1695-1706.
doi: 10.4155/cli.11.150.

Src inhibitors in the treatment of metastatic bone disease: rationale and clinical data

Brendan Boyce  1 , Lianping Xing
Affiliations

Src inhibitors in the treatment of metastatic bone disease: rationale and clinical data

Brendan Boyce et al. Clin Investig (Lond). .

Abstract

Src is a nonreceptor tyrosine kinase essential for the activation of osteoclasts, the cells that degrade bone. Src also regulates normal cell functions, cancer cell growth and metastasis to organs, including bone where tumor cells induce bone destruction by osteoclasts. Src inhibitors prevent bone destruction and tumor cell growth in animal models of metastatic bone disease, and some are being investigated in clinical trials, particularly in patients with prostate cancer, which has high bone metastatic potential. Here, we review how Src regulates osteoclast formation, activation and survival and the results of preclinical and clinical trials of Src inhibitors, which show some promise in inhibiting the effects of tumor cells on the skeleton.

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Figures

Figure 1
Figure 1. Osteoclast resorbing bone
The ruffled border formed on the underside of the osteoclast facing the bone increases the surface area of the cell. The clear zone surrounds the ruffled border and seals the resorbing compartment. Hydrochloric acid is formed in the cavity following active transfer of H+ by a proton pump (the vacuolar-type H+-ATPase) and passage of Cl− via a Cl− channel, and proteolytic enzymes are released passively from the osteoclast into the cavity to dissolve the mineral and matrix components of bone, respectively. (Section of calvarial bone from a mouse treated with IL-1 and stained for tartrate-resistant acid phosphatase activity with hematoxylin counterstaining). MMP: Matrix metalloproteinase.
Figure 2
Figure 2. A vicious cycle of tumor cell-induced resorption and resorption-induced tumor growth
Tumor cells metastasize to the bone marrow where Src signaling mediates their growth and movement within the marrow cavity. The tumor cells secrete osteoclast-stimulating factors, including PTHrP, which stimulate osteoclast formation and activation by inducing expression of RANKL by osteoblastic stromal cells within the marrow. Osteoclasts resorb the bone, releasing growth factors, including TGF-β and FGFs, which stimulate tumor cell proliferation. TGF-β also induces expression of PTHrP by the tumor cells. Src regulates various functions of cancer cells and osteoclasts, and Src inhibition could reduce growth of metastatic cancer cells in bone by disrupting this vicious cycle.
Figure 3
Figure 3. Src tyrosine kinase structural domains
The Src protein has three major structural domains that mediate its functions: the SH2 domain to which molecules with tyrosine residues bind; the SH3 domain, which binds proline-rich portions of interacting molecules, and the kinase domain, which phosphorylates tyrosines on target proteins. Autophosphorylation of tyrosine 416 keeps the Src kinase in an active conformation while phosphorylation of tyrosine 527 has the opposite effect. Tyrosine 295 (K295) is in the ATP-binding site and is essential for Src kinase activity. The N-terminal region of Src is M, which allows it to be associated with the cell membrane. M: Myristoylated; SH: Src homology.
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References

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    1. Boyce BF, Yoneda T, Lowe C, Soriano P, Mundy GR. Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J. Clin. Invest. 1992;90(4):1622–1627. ■■ Examines the potential mechanisms whereby Src expression in osteoclasts was required for bone resorption. It reported that formation of the ruffled border membrane, a characteristic morphologic feature of activated osteoclasts, requires Src expression in osteoclasts.

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