In Cancer Discovery this week, Novartis researchers report on how secreted proteins may induce resistance to kinase inhibitors in some cancer patients. The team developed a high-throughput platform for screening a cDNA library encoding 3,482 secreted proteins in cellular assays. "Using cancer cells originally dependent on either MET, FGFR2, or FGFR3, we observed a bypass of dependence through ligand-mediated activation of alternative [receptor tyrosine kinases]," the authors write. "Our findings indicate a broad and versatile potential for RTKs from the HER and FGFR families as well as MET to compensate for loss of each other." This also suggests that combination treatments to inhibit several active receptor tyrosine kinases at the same time can lead to further anti-cancer effects.
Also in Cancer Discovery this week, a team of US researchers led by the University of Massachusetts Medical School's Hira Lal Goel describe a novel mechanism of aggressive prostate cancer. The team found that VEGF receptor neuropilin-2 is associated with high-grade, PTEN-null prostate cancer, "and that its expression in tumor cells is induced by PTEN loss as a consequence of c-Jun activation." Goel et al. observed that VEGF/NRP2 signaling represses the expression and signaling of IGF-1R through a mechanism that involves Bmi-1-mediated transcriptional repression of the IGF-1R. "This mechanism has significant functional and therapeutic implications that were evaluated," the authors write. "IGF-1R expression correlates with PTEN and inversely with NRP2 in prostate tumors. NRP2 is a robust biomarker for predicting response to IGF-1R therapy because prostate carcinomas that express NRP2 exhibit low levels of IGF-1R."