BERKELEY, CA (UroToday.com) - In Clinical Cancer Research, Dr. Juan Carlos Montero and Spanish colleagues discuss inhibition of tyrosine kinases (TKs) in solid tumors, including prostate cancer (CaP). Src kinase is the first described oncogene in the early 1980s.
It is a non-receptor TK that regulates numerous cellular properties and is overexpressed in many cancers. Dasatinib is a small molecule inhibitor or Src/Abl that is approved for clinical use in chronic myelogenous leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia. Dasatinib actively inhibits cell duplication in numerous solid tumors including triple negative breast cancer, gastric, pancreatic, and head and neck tumor lines. It also inhibits tumor cell motility and metastatic dissemination. This is in part due to its inhibition of the activation of focal adhesion kinase (FAK) and effects on cytoskeletal components. The drug is also active in tumors that metastasize to bone, where osteoclasts express Src. Inhibition of both tumor cells and osteoclasts in this setting inhibit the vicious cycle of breast and prostate cancer bone metastases.
Single agent targeted therapies in the advanced disease setting are often best tested as part of combination therapy. One example is the combination with human epidermal growth factor receptor (HER) inhibitors as both are often activated in cancers and Src is involved in HER signaling, and the combination demonstrated effectiveness in breast cancer models. Dasatinib has also shown synergy with anti-EGFR monoclonal antibodies and STAT3 inhibitors. Markers of response and resistance to dasatinib have been identified. Activated forms of the kinases indicate tumor sensitivity to dasatinib. Gene arrays have also been identified. For example a dasatinib sensitivity signature was identified in CaP patients with low androgen receptor activity.
In CaP, Src family kinases and FAK are activated and correlated with poor patient outcome and poor response to anti-hormonal therapies. Animal models have shown decrease in primary tumor growth, decreased metastasis to lymph nodes and bone and decreased bone destruction. In a phase I-II trial using PCWG 2 response criteria, dasatinib demonstrated clinical activity in castration-resistant prostate cancer that was chemotherapy naïve. Another phase I-II study evaluated dasatinib in combination with docetaxel - 42% of patients had a partial response and 68% had a partial response or stable disease for more than 18 weeks. Half of patients had a PSA response. Presently there is an ongoing phase III trial randomizing patients to docetaxel alone or in combination with dasatinib, 100mg orally every day.
Montero JC, Seoane S, Ocaña A, Pandiella A
Clin Cancer Res. 2011 Sep 1;17(17):5546-52
10.1158/1078-0432.CCR-10-2616
PubMed Abstract
PMID: 21670084
UroToday.com Prostate Cancer Section
