The Notch and Hedgehog pathways are upregulated in docetaxel-resistant HRPC.
Major finding: The Notch and Hedgehog pathways are upregulated in docetaxel-resistant HRPC.
Concept: Docetaxel-resistant cells have tumor-initiating capacity and are associated with poor prognosis.
Impact: Combined use of Notch and Hedgehog pathway inhibitors may improve docetaxel efficacy in HRPC.
The antimitotic agent docetaxel is the standard therapy for patients with hormone-refractory prostate cancer (HRPC), but fatal resistance ultimately develops despite an initial response. Domingo-Domenech and colleagues generated docetaxel-resistant HRPC cell lines to gain insight into the underlying resistance mechanisms and identify potential targets to prevent the development of docetaxel resistance in HRPC. Docetaxel-resistant cells showed downregulation of epithelial differentiation markers such as cytokeratins (CK) and a marked upregulation of developmental genes in the Notch and Hedgehog signaling pathways. To determine whether these observations had clinical relevance, the authors evaluated a panel of primary and metastatic prostate cancer samples and identified a small subpopulation of preexisting CK-negative cells with upregulated Notch and Hedgehog signaling in each tumor. Of note, these cells were more abundant in samples from patients with advanced disease and a higher percentage of CK-negative cells was associated with a worse clinical outcome. The CK-negative subpopulation with upregulated Notch and Hedgehog signaling also expanded in patients who had received docetaxel treatment and was shown to have potent tumor-initiating activity, further suggesting that eradicating this cell population with Notch and Hedgehog pathway inhibitors would have clinical benefit. Indeed, combined genetic or pharmacologic inhibition of Notch and Hedgehog signaling inhibited colony formation of docetaxel-resistant HSPC cells, due to inhibition of the prosurvival proteins AKT and BCL-2. Furthermore, use of Notch and Hedgehog inhibitors in combination with docetaxel potently suppressed the growth of HRPC xenografts more than any individual agent. Together, these results provide a rationale for the development of Notch and Hedgehog inhibitors as a strategy to prevent acquired docetaxel resistance and extend survival in patients with HRPC.