Abstract
The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug resistance. To address this issue, we systematically assessed the potential of secreted proteins to induce resistance to kinase inhibitors. To this end, we developed a high-throughput platform for screening a cDNA library encoding 3,432 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 (RTK). 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. We further provide evidence that combined inhibition of simultaneously active RTKs can lead to an added anticancer effect.
Highlights
Genetic alterations, including point mutations, gene amplifications, and chromosomal translocations, can render kinases oncogenic [1, 2]
These cDNAs, representing 2,803 genes predicted to encode secreted proteins, were individually transfected into HEK293T cells in 384-well plates to obtain cell culture supernatants where each well was expected to contain a defined secreted protein (Fig. 1A). The ability of these supernatants to abrogate growth inhibition was tested by transferring the supernatants to wells containing cancer cells addicted to a specific oncogene and for which a selective inhibitor was available
We found that several members of the fibroblast growth factor (FGF) family could rescue MKN-45 cells
Summary
Genetic alterations, including point mutations, gene amplifications, and chromosomal translocations, can render kinases oncogenic [1, 2]. The term “oncogene addiction” has been used to describe the phenomenon in which growth and survival of cancer cells becomes dependent on an aberrantly activated protein, for example, a kinase [3, 4]. One mechanism of resistance involves mutation of the target, thereby compromising binding and activity of the therapeutic agent. Efforts to understand the specific mechanisms of resistance to imatinib in chronic myelogenous leukemia have led to second-generation inhibitors (e.g., nilotinib) that treat and prevent resistance through increased potency. The discovery of parallel or downstream bypass mechanisms of resistance are motivating novel combination therapies as a means to prevent such bypass events
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