Signaling and Feedback Networks Underlying Senstivity and Resistance to Kinase Inhibitors in Oncogene Addicted Cancers
Contributors: Engelman, Jeffrey A.; Fisher, David; Janne, Pasi; Cantley, Lewis; Settleman, Jeffrey
Published: 2012
Language: eng
Description: 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.
Notes: Keywords: feedback, kinase inhibitor, PI3K, receptor, resistance.

Thesis Ph.D. Harvard University 2011