EGFR mutant lung cancer is a subset of lung cancer with unique biological and clinical features. Over 70% of patients whose lung cancers harbor specific mutations within the exons encoding the tyrosine kinase domain of EGFR experience radiographic responses to the selective EGFR tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or eriotinib (Tarceva), and overall median survival is about 30 months. However, no patients are cured. After about one year, acquired resistance develops. In previous work, we showed that in addition to primary drug-sensitive EGFR mutations, tumor cells from more than half of patients with such "acquired resistance" contain a recurrent second-site mutation (T790M) in the EGFR kinase domain. We also demonstrated using mouse models of lung cancer that T790M-mediated resistance could be overcome by a novel combination ofthe second-generation EGFR TKI, afatinib (BIBW2992), and the anti-EGFR antibody, cetuximab. A Phase IB clinical trial ofthis combination in humans, based upon our data, has now shown unprecedented activity in this patient cohort, with a 95% clinical benefit rate and a 35% confirmed radiographic response rate. The clinical findings have stimulated new and critical biological questions to address. Here, based upon promising new preliminary data, we aim to 1) elucidate the role of HER2 in mediating sensitivity of T790M-harboring EGFR mutant lung cancer cells to afatinib/cetuximab, and 2) identify in EGFR mutant kinases intrinsic regulatory domains required for full kinase function. An improved understanding of mechanisms and modulators of sensitivity and resistance to EGFR inhibitors will hopefully allow us to treat/suppress the development of progressive disease and provide new insights into the biology of cancers driven by EGFR or other mutant receptor tyrosine kinases.
Lung cancers are America's leading cancer killers, responsible for 158,000 deaths this year. This grant addresses the two most critical roadblocks to improving the care and curability of persons with these illnesses: (1) understanding how cancers spread (metastasis) and (2) the lack of highly effective medicines to prevent spread or to eradicate cancers that have spread from the lung.
|Chen, Qing; Boire, Adrienne; Jin, Xin et al. (2016) Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533:493-8|
|Hames, Megan L; Chen, Heidi; Iams, Wade et al. (2016) Correlation between KRAS mutation status and response to chemotherapy in patients with advanced non-small cell lung cancerâ˜†. Lung Cancer 92:29-34|
|Amato, Katherine R; Wang, Shan; Tan, Li et al. (2016) EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer. Cancer Res 76:305-18|
|Lito, Piro; Solomon, Martha; Li, Lian-Sheng et al. (2016) Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 351:604-8|
|Malladi, Srinivas; Macalinao, Danilo G; Jin, Xin et al. (2016) Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT. Cell 165:45-60|
|Konduri, Kartik; Gallant, Jean-Nicolas; Chae, Young Kwang et al. (2016) EGFR Fusions as Novel Therapeutic Targets in Lung Cancer. Cancer Discov 6:601-11|
|Dragani, Tommaso A; Castells, Antoni; Kulasingam, Vathany et al. (2016) Major milestones in translational oncology. BMC Med 14:110|
|Manchado, Eusebio; Weissmueller, Susann; Morris 4th, John P et al. (2016) A combinatorial strategy for treating KRAS-mutant lung cancer. Nature 534:647-51|
|Johnson, Douglas B; Estrada, Monica V; Salgado, Roberto et al. (2016) Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat Commun 7:10582|
|MassaguÃ©, Joan; Obenauf, Anna C (2016) Metastatic colonization by circulating tumour cells. Nature 529:298-306|
Showing the most recent 10 out of 157 publications