Dependency on Src-Family Kinases for Recurrence of Androgen-Independent Prostate Cancer
Abstract
Prostate cancers that recur after so-called androgen-ablation therapy ( CR-CaP ) are typically more aggressive, more likely to spread to local lymph nodes and bones, and less likely to respond to second-tier treatments, and therefore, contribute to significantly decreased patient survival. We posit that enzymes called Src-family kinases (SFK) are required for the progression to CR-CaP, and thus, targeting these enzymes should prevent CR-CaP formation of suppress their growth. We have shown that inhibition of Src or Lyn by shRNA or drugs (Dasatinib or KX2-391) significantly decreases the frequency and time-to-formation of CR-CaP in the CWR22 model, and primary prostate cancer formation in the TRAMP mouse model. CRCaP lesions that arose after Src knockdown exhibited parental levels of Src proteins, suggesting that Src is required for CRCaP formation. Interestingly, the loss of Fyn enhanced the ability of TRAMP mice to form CaP lesions. Our pre-clinical studies identify role for certain SFK members, such as Src and Lyn, in CR-CaP disease. However, the therapeutic targeting of SFK in CR-CaP will likely require more specific inhibitors than Dasatinib so as not to also target SFK members such as Fyn, which might have CR-suppressing roles. This study, nonetheless, serves as a justification for the use of KX2-391 to treat or preventCRCaP.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2012
- Accession Number
- ADA566985
Entities
People
- Irwin H Gelman
Organizations
- Health Research, Incorporated