Rescue Screens with Secreted Proteins Reveal Compensatory Potential of Receptor Tyrosine Kinases in Driving Cancer Growth

Cancer Discovery - Tập 2 Số 10 - Trang 948-959 - 2012
Fred Harbinski1, Vanessa J. Craig1, Sneha Sanghavi1, Douglas A. Jeffery1, Lijuan Liu1, Kelly-Ann Sheppard1, Sabrina Wagner1, Christelle Stamm1, Andreas Buneß1, Christian Chatenay‐Rivauday1, Yao Yao1, Feng He1, Chris X. Lu1, Vito Guagnano1, Thomas Metz1, Peter M. Finan1, Francesco Hofmann1, William R. Sellers1, Jeffrey A. Porter1, Vic E. Myer1, Diana Graus-Porta1, Christopher J. Wilson1, Alan Buckler1, Ralph Tiedt1
1Authors' Affiliations: 1Developmental and Molecular Pathways and 2Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts; 3Disease Area Oncology and 4Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland; 5Oncology Translational Medicine, 6Global Discovery Chemistry, and 7Developmental and Molecular Pathways, China Novartis Institutes for BioMedical Research, Shanghai, PR China; and 8Oncotest GmbH, Freiburg, Germany

Tóm tắt

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. Significance: Although initial tumor responses to kinase inhibitors can be significant, therapeutic benefit is often limited by the emergence of resistance (e.g., as a consequence of mutations in the drug target or through activation of alternative pathways to bypass dependence on the original target). Because the activation of alternative growth-promoting kinases by stimulation with their cognate ligands can constitute such a bypass mechanism, the identification of growth factors as possible mediators of resistance to kinase inhibitors is of clinical interest. Cancer Discov; 2(10); 948–59. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 857.

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Cancer Discovery

Tập 2 Số 10

948-959

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