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Rescue screens with secreted proteins reveal compensatory potential of receptor tyrosine kinases in driving cancer growth

Harbinski, Fred and Craig, Vanessa and Sanghavi, Sneha and Jeffery, Douglas and Liu, Lijuan and Sheppard, Kelly-Ann and Wagner, Sabrina and Stamm, Christelle and Buness, Andreas and Chatenay-Rivauday, Christian and Metz, Thomas and Finan, Peter and Hofmann, Francesco and Sellers, William and Porter, Jeffrey and Myer, Vic and Yao, Yao and Graus Porta, Diana and Wilson, Christopher and Buckler, Alan and Tiedt, Ralph (2012) Rescue screens with secreted proteins reveal compensatory potential of receptor tyrosine kinases in driving cancer growth. Cancer Discovery. ISSN 2159-8274

Abstract

Oncogenic alterations of kinases are a frequent cause of cancer growth. Accordingly, inhibition of such “driver” kinases is a clinically proven anti-cancer therapeutic approach. While initial responses to kinase inhibitors can be significant, the emergence of resistance often limits therapeutic benefit. Resistance mechanisms that have been discovered in relapse samples include mutations in the drug target or activation of alternative pathways to bypass dependence on the original target. In the case of kinases, bypass can occur through activation of an alternative growth-promoting kinase that compensates for inhibition of the original driver kinase. Several known oncogenic kinases belong to the family of receptor tyrosine kinases (RTK). Besides genetic alterations like mutation, gene amplification, or translocation, RTK activation also occurs by stimulation with its cognate ligands. Such RTK activation can be autocrine or paracrine, depending on whether the ligands are produced by the tumors themselves or originate from surrounding cells in the tumor microenvironment. Here, we systematically assessed the potential of secreted proteins to induce resistance to kinase inhibitors in cellular screens. To this end a cDNA library encoding 3482 secreted proteins was transfected into a producer cell line. Supernatants were then transferred to several RTK-dependent cancer cell lines that were concomitantly treated with a corresponding kinase inhibitor in order to determine which supernatants could prevent growth inhibition. Using cancer cells originally dependent on either MET, FGFR2, or FGFR3, we observed a bypass of dependence through ligand-mediated activation of alternative RTKs. 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 added anti-cancer effect.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/6642

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