Bypass Pathways Allow Some Cancers To Resist Kinase Inhibitor Drugs Interview with:
Douglas.A. Lauffenburger PhD
Ford Professor of Biological Engineering, Chemical Engineering, and Biology
Head, Department of Biological Engineering
Massachusetts Institute of Technology
Cambridge, MA 02139 What is the background for this study? What are the main findings?

Dr. Lauffenburger: We aimed to advance understanding concerning causes of tumor resistance to kinase inhibitor drugs, which limits effectiveness for many therapeutics even when indicated by specific genetic mutations in the new ‘personalized medicine’ paradigm.  We discovered a new mechanism underlying this resistance at least for a number of otherwise promising drugs currently in clinical use as well as further clinical trials.  Our discovery was based on realizing that the same oncogenic signaling driving tumor cell proliferation and invasiveness at the same time activates proteolytic shedding of receptor tyrosine kinases not involved in the targeted oncogenic pathway, shutting down additional signaling inputs.  Thus, when the targeted pathway is inhibited by the intended drug, this shedding is concomitantly diminished — now permitting “bypass” pathways to be activated downstream of these alternative receptor inputs.  Moreover, we showed that measurement of a set of key shed receptors (primarily AXL and MET, in our examined case of MEK pathway inhibitors for melanoma and triple-negative breast tumors) in patient blood serum samples could predict effectiveness of these inhibitors: when the shed levels were high, the drugs were less effective because of the correspondingly great potential for bypass signaling upon drug treatment.  In follow-up mouse experiments, we demonstrated increased effectiveness of a MEK inhibitor when combined with either an AXL inhibitor or a proteolysis inhibitor, thereby confirming the mechanism and proving an avenue for overcoming it. What should clinicians and patients take away from your report?

Dr. Lauffenburger: One promising finding for translational application was that measurement of the key shed receptor tyrosine kinases in blood serum may be predictive of kinase inhibitor effectiveness.  Another was identification of AXL as an especially beneficial target for combination therapy in association with a kinase pathway inhibitor. What recommendations do you have for future research as a result of this study?

Dr. Lauffenburger: A more general lesson from this study is that some important determinants of drug effectiveness in the personalized medicine era may not necessarily be identified simply from genomic information, but instead will require protein-level understanding of cellular mechanisms. Is there anything else you would like to add?

Dr. Lauffenburger: This work was undertaken in close collaboration between investigators in the Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology and in the Termeer Center for Targeted Therapies at Massachusetts General Hospital. Thank you for your contribution to the community.


Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance

Miles A. Miller, Madeleine J. Oudin, Ryan J. Sullivan, Stephanie J. Wang,Aaron S. Meyer, Hyungsoon Im, Dennie T. Frederick, Jenny Tadros,Linda G. Griffith, Hakho Lee, Ralph Weissleder, Keith T. Flaherty, Frank B. Gertler,and Douglas A. Lauffenburger

Cancer Discov Published OnlineFirst March 16, 2016;

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Douglas.A. Lauffenburger PhD (2016). Bypass Pathways Allow Some Cancers To Resist Kinase Inhibitor Drugs