Cancer research
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The receptor tyrosine kinase c-Met is an attractive target for therapeutic blockade in cancer. Here, we describe MK-2461, a novel ATP-competitive multitargeted inhibitor of activated c-Met. MK-2461 inhibited in vitro phosphorylation of a peptide substrate recognized by wild-type or oncogenic c-Met kinases (N1100Y, Y1230C, Y1230H, Y1235D, and M1250T) with IC(50) values of 0.4 to 2.5 nmol/L. ⋯ In a murine xenograft model of c-Met-dependent gastric cancer, a well-tolerated oral regimen of MK-2461 administered at 100 mg/kg twice daily effectively suppressed c-Met signaling and tumor growth. Similarly, MK-2461 inhibited the growth of tumors formed by s.c. injection of mouse NIH-3T3 cells expressing oncogenic c-Met mutants. Taken together, our findings support further preclinical development of MK-2461 for cancer therapy.
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Androgen-deprivation therapy for prostate cancer (PC) eventually leads to castration-resistant PC (CRPC). Intratumoral androgen production might contribute to tumor progression despite suppressed serum androgen concentrations. In the present study, we investigated whether PC or CRPC tissue may be capable of intratumoral androgen synthesis. ⋯ AKR1C3 expression was negatively regulated by androgens in the experimental models and was increased in CRPC samples. Expression of SRD5A1 was upregulated in locally advanced cancer, CRPC, and lymph node metastases. We concluded that intratumoral steroid biosynthesis contributes less than circulating adrenal androgens, implying that blocking androgen production and its intraprostatic conversion into DHT, such as via CYP17A1 inhibition, may represent favorable therapeutic options in patients with CRPC.