The clinical success of EGFR kinase inhibitors gefitinib and eriotinib in EGFR mutant non-small cell lung cancer (NSCLC) is limited by the eventual development of acquired drug resistance. We and others have identified two main mechanisms of drug resistance: acquired secondary mutations in EGFR (EGFR T790M) and activation of HGF/MET signaling (either by MET amplification or by autocrine/paracrine production of HGF). In both instances, the resistant cancers maintain dependence on EGFR signaling, highlighting the need to develop novel EGFR-targeted therapies and/or combination therapeutic approaches. Irreversible quinazoline-based EGFR kinase inhibitors, including HKI-272, PF00299804. and B1BW2992, are effective in some preclinical models against EGFR T790M, but clinically their efficacy has been limited by lack of potency and toxicity (skin rash and diarrhea) due to concurrent on-target inhibition of wild-type (WT) EGFR. Recentiy, we identified irreversible pyrimidine EGFR kinase inhibitors (WZ4002) that are selective for the mutant EGFR receptor and are significantiy more potent against EGFR T790M than existing irreversible quinazoline EGFR inhibitors. Furthermore, these agents, unlike quinazoline irreversible EGFR inhibitors, prevent the emergence of EGFR T790M as a resistance mechanism using in vitro models. Although this new class of EGFR inhibitors may be clinically more effective than currentiy available agents, resistance is nevertheless expected to also develop to all irreversible EGFR inhibitors. In fact, a mutation in the covalent binding site (C797S) of EGFR alone is sufficient to cause resistance to both WZ4002 and HKI-272. In this project we propose to develop additional agents that can effectively inhibit EGFR in the presence of the C797S and other drug resistance mutations.
The specific aims are 1.) Characterize EGFR small molecule kinase inhibitors against irreversible EGFR kinase inhibitor resistance mutations. 2.) Identify resistance mechanisms to irreversible pyrimidine EGFR inhibitors and 3.) Determine the impact of targeting drug resistance mechanisms on the efficacy of irreversible pyrimidine EGFR inhibitors and the emergence of drug resistance.
EGFR kinase inhibitors are effective clinical therapies for 30,000 patients in the United States diagnosed annually with EGFR mutant NSCLC. However, acquired drug resistance ultimately develops on all patients. Identification of effective therapies to treat drug resistant cancers is of great clinical and public health importance. We will synthesize and validate novel EGFR kinase inhibitors that may serve as novel therapies for EGFR mutant NSCLC.
|Gannon, Hugh S; Kaplan, Nathan; Tsherniak, Aviad et al. (2016) Identification of an ""Exceptional Responder"" Cell Line to MEK1 Inhibition: Clinical Implications for MEK-Targeted Therapy. Mol Cancer Res 14:207-15|
|Jia, Yong; Yun, Cai-Hong; Park, Eunyoung et al. (2016) Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 534:129-32|
|Kim, Eejung; Ilic, Nina; Shrestha, Yashaswi et al. (2016) Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles. Cancer Discov 6:714-26|
|Aguirre, Andrew J; Meyers, Robin M; Weir, Barbara A et al. (2016) Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting. Cancer Discov 6:914-29|
|Zhang, Haikuo; Qi, Jun; Reyes, Jaime M et al. (2016) Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer. Cancer Discov 6:1006-21|
|Yang, Shenghong; Imamura, Yu; Jenkins, Russell W et al. (2016) Autophagy Inhibition Dysregulates TBK1 Signaling and Promotes Pancreatic Inflammation. Cancer Immunol Res 4:520-30|
|Wu, Hong; Wang, Aoli; Zhang, Wei et al. (2015) Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells. Oncotarget 6:31313-22|
|Lim, Sang Min; Xie, Ting; Westover, Kenneth D et al. (2015) Development of small molecules targeting the pseudokinase Her3. Bioorg Med Chem Lett 25:3382-9|
|Tricker, Erin M; Xu, Chunxiao; Uddin, Sharmeen et al. (2015) Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung Cancer. Cancer Discov 5:960-71|
|Shen, R R; Zhou, A Y; Kim, E et al. (2015) TRAF2 is an NF-*B-activating oncogene in epithelial cancers. Oncogene 34:209-16|
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