Oncogenic genomic alterations in non-small cell lung cancer (NSCLC) are excellent therapeutic targets. Compelling clinical examples include somatic mutations in the epidermal growth factor receptor (EGFR) and in anaplastic lymphoma kinase (ALK) rearrangements. In both instances, treatment with specific kinase inhibitors, erlotinib (EGFR) and crizotinib (ALK), results in improved outcomes compared to systemic chemotherapy for patients with advanced EGFR mutant or ALK rearranged NSCLC, and are the standard of care first line therapies. However, the therapeutic benefit is limited (8 to 12 months): currently no patient is cured and all patients wll ultimately develop acquired drug resistance. Drug resistance to kinase inhibitors occurs by two types of mechanisms: i) secondary mutations in the kinase target or ii) activation of a bypass signaling pathway. In both cases, downstream signaling pathways become reactivated despite the presence of the kinase inhibitor. In EGFR mutant NSCLC, EGFR T790M secondary mutation is the most common mechanism, detected in 50-60% of cancers from EGFR mutant patients that develop clinical resistance to erlotinib. Bypass mechanisms include activation of MET (through MET amplification or by HGF) and AXL signaling. To date, clinical therapies for EGFR mutant erlotinib resistant NSCLC patients have been ineffective. These observations are likely due to i) lack of effective therapeutic agents against EGFR T790M, ii) incomplete understanding of the heterogeneity of drug resistance in patients, and iii) inability to develop strategies to inhibit multiple drug resistane mechanisms simultaneously. We have previously shown that we can overcome resistance conferred by EGFR T790M mutations in preclinical models with irreversible EGFR inhibitors. However, current clinical irreversible quinazoline EGFR inhibitors, including afatinib and dacomitinib, although effective in some preclinical models harboring EGFR T790M, are not effective in EGFR T790M NSCLC patients. One possible explanation for these observations may lie in the fact that afatinib and dacomitinib are very good inhibitor of wild type (WT) EGFR. As such, inhibition of WT EGFR results in on-target toxicity, skin rash, which prevents clinical administration of doses high enough to inhibit EGFR T790M. In order to overcome this limitation, we have developed two pre-clinical strategies: i.) intermittet pulsatile administration of dacomitinib to transiently but effectively inhibit EGFR T79M and ii.) identification of the first in class mutant selective EGFR inhibitor, WZ4002. Both strategies are currently being evaluated in clinical trials. Here we propose critical studies that will inform the clinical development of these and future treatment strategies by comprehensively studying heterogeneity of drug resistance mechanisms, developing novel combination strategies with WZ4002 informed by drug resistance mechanisms, and developing clinical trial-based biomarkers for improved evaluation of the evolution and treatment of drug resistance.

Public Health Relevance

The development of drug resistance limits the long term success of epidermal growth factor receptor (EGFR) inhibitors in EGFR mutant lung cancer patients. By studying the genomic landscape of drug resistant cancers and plasma derived DNA from lung cancer patients coupled with the development of therapeutic strategies which can be clinically implemented in the near term, the studies in this proposal aim to improve the outcome of EGFR mutant lung cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA135257-09
Application #
9057459
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Timmer, William C
Project Start
2008-08-01
Project End
2018-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
9
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
Bahcall, Magda; Awad, Mark M; Sholl, Lynette M et al. (2018) Amplification of Wild-type KRAS Imparts Resistance to Crizotinib in MET Exon 14 Mutant Non-Small Cell Lung Cancer. Clin Cancer Res 24:5963-5976
Lizotte, Patrick H; Hong, Ruey-Long; Luster, Troy A et al. (2018) A High-Throughput Immune-Oncology Screen Identifies EGFR Inhibitors as Potent Enhancers of Antigen-Specific Cytotoxic T-lymphocyte Tumor Cell Killing. Cancer Immunol Res 6:1511-1523
Oxnard, Geoffrey R; Hu, Yuebi; Mileham, Kathryn F et al. (2018) Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib. JAMA Oncol 4:1527-1534
Chong, Curtis R; Bahcall, Magda; Capelletti, Marzia et al. (2017) Identification of Existing Drugs That Effectively Target NTRK1 and ROS1 Rearrangements in Lung Cancer. Clin Cancer Res 23:204-213
Kosaka, Takayuki; Tanizaki, Junko; Paranal, Raymond M et al. (2017) Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors. Cancer Res 77:2712-2721
Saxon, Jamie A; Sholl, Lynette M; Jänne, Pasi A (2017) EGFR L858M/L861Q cis Mutations Confer Selective Sensitivity to Afatinib. J Thorac Oncol 12:884-889
Bahcall, Magda; Sim, Taebo; Paweletz, Cloud P et al. (2016) Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer. Cancer Discov 6:1334-1341
Paweletz, Cloud P; Sacher, Adrian G; Raymond, Chris K et al. (2016) Bias-Corrected Targeted Next-Generation Sequencing for Rapid, Multiplexed Detection of Actionable Alterations in Cell-Free DNA from Advanced Lung Cancer Patients. Clin Cancer Res 22:915-22
Oxnard, Geoffrey R; Thress, Kenneth S; Alden, Ryan S et al. (2016) Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 34:3375-82
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

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