Signaling and Feedback Networks Underlying Senstivity and Resistance to Kinase Inhibitors in Oncogene Addicted Cancers

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Signaling and Feedback Networks Underlying Senstivity and Resistance to Kinase Inhibitors in Oncogene Addicted Cancers

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Title: Signaling and Feedback Networks Underlying Senstivity and Resistance to Kinase Inhibitors in Oncogene Addicted Cancers
Author: Schrock, Alexa
Citation: Schrock, Alexa. 2011. Signaling and Feedback Networks Underlying Senstivity and Resistance to Kinase Inhibitors in Oncogene Addicted Cancers. Doctoral dissertation, Harvard University.
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Abstract: Targeted therapies have begun to be developed and approved in the clinic over the past several decades to treat cancers with specific genetic alterations. In non-small cell lung cancer (NSCLC), patients harboring EGFR activating mutations often respond to the EGFR inhibitors gefitinib/erlotinib, exhibiting down-regulation of central oncogenic pathways and dramatic tumor regressions. Despite initially promising results, the vast majority of patients develop resistance to targeted therapies. Thus far, several mechanisms of resistance including T790M mutation in EGFR, amplification of the MET receptor tyrosine kinase (RTK), activating mutations in downstream signaling molecules, and loss of negative regulators have been identified. As a result, next generation inhibitors and combination therapies continue to be developed and tested in the clinic. There are still many cases in which the cause of resistance to a particular targeted therapy is unknown, or the subset of patients most likely to benefit has not been identified. This thesis describes the ability of the MET ligand, HGF, to activate PI3K signaling and cause gefitinib resistance in EGFR-driven cancers. In addition, detection of a preexisting subpopulation of MET amplified cells (present before treatment with an EGFR inhibitor) is shown to successfully predict the development of MET amplification as a resistance mechanism. These results suggest that it may be possible to prospectively identify patients who will benefit from combined MET/HGF and EGFR inhibitors as initial therapies. Further, this thesis highlights the importance of both PI3K/AKT and MEK/ERK signaling as drivers of cell proliferation and viability, and describes a novel feedback network regulating these pathways. In multiple cancer models, treatment with a single agent MEK inhibitor leads to feedback up-regulation of ERBB3/PI3K/AKT signaling. The mechanism for this feedback involves loss of an inhibitory threonine phosphorylation in the conserved juxtamembrane domains of EGFR and HER2 following MEK inhibition, which leads to increased ERBB receptor activation. These results further elucidate the complex feedback networks that regulate signaling in cancer cells, and suggest possible limitations for the efficacy of single agent RAF/MEK pathway inhibitors. Collectively, this work describes multiple resistance mechanisms to kinase inhibitors, and suggests new biomarkers to define those patients who are likely to benefit from specific targeted therapies.
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Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10121967
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