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.
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.
|Chong, Curtis R; Wirth, Lori J; Nishino, Mizuki et al. (2014) Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors. Lung Cancer 86:241-6|
|Oxnard, Geoffrey R; Paweletz, Cloud P; Kuang, Yanan et al. (2014) Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res 20:1698-705|
|Kawabata, Shigeru; Mercado-Matos, José R; Hollander, M Christine et al. (2014) Rapamycin prevents the development and progression of mutant epidermal growth factor receptor lung tumors with the acquired resistance mutation T790M. Cell Rep 7:1824-32|
|Sacher, Adrian G; Jänne, Pasi A; Oxnard, Geoffrey R (2014) Management of acquired resistance to epidermal growth factor receptor kinase inhibitors in patients with advanced non-small cell lung cancer. Cancer 120:2289-98|
|Cortot, Alexis B; Repellin, Claire E; Shimamura, Takeshi et al. (2013) Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway. Cancer Res 73:834-43|
|Chong, Curtis R; Jänne, Pasi A (2013) The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med 19:1389-400|
|Oxnard, Geoffrey R; Lo, Peter C; Nishino, Mizuki et al. (2013) Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol 8:179-84|
|Faber, Anthony C; Corcoran, Ryan B; Ebi, Hiromichi et al. (2011) BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discov 1:352-65|
|Qi, Jie; McTigue, Michele A; Rogers, Andrew et al. (2011) Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors. Cancer Res 71:1081-91|
|Janne, Pasi A; Boss, David S; Camidge, D Ross et al. (2011) Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res 17:1131-9|
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