Establishment and antitumor effects of dasatinib and PKI 587 in BD 138T, a patient derived muscle invasive bladder cancer preclinical platform with concomitant EGFR amplification and PTEN deletion
Muscle invasive bladder cancer (MIBC) consists of a heterogeneous group of tumors with a high rate of metastasis and mortality. To facilitate the in depth investigation and validation of tailored strategies for MIBC treatment, we have developed an integrated approach using advanced high throughput drug screening and a clinically relevant patient derived preclinical platform. We isolated patient derived tumor cells (PDCs) from a rare MIBC case (BD 138T) that harbors concomitant epidermal growth factor receptor (EGFR) amplification and phosphatase and tensin homolog (PTEN) deletion. High throughput in vitro drug screening demonstrated that dasatinib, a SRC inhibitor, and PKI 587, a dual PI3K/mTOR inhibitor, exhibited targeted anti proliferative and pro apoptotic effects against BD 138T PDCs. Using established patient derived xenograft models that successfully retain the genomic and molecular characteristics of the parental tumor, we confirmed that these anti tumor responses occurred through the inhibition of SRC and PI3K/AKT/mTOR signaling pathways. Taken together, these experimental results demonstrate that dasatinib and PKI 587 might serve as promising anticancer drug candidates for treating MIBC with combined EGFR gene amplification and PTEN deletion.
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