Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1
Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR -mutant lung cancers. Here, we modeled disease progression using EGFR -mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 31; pp. E2127 - E2133 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
31.07.2012
National Acad Sciences |
| Series | PNAS Plus |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR -mutant lung cancers. Here, we modeled disease progression using EGFR -mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS / RAF / MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS , KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR -mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment. |
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| AbstractList | Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR -mutant lung cancers. Here, we modeled disease progression using EGFR -mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS / RAF / MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS , KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR -mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment. Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment. [PUBLICATION ABSTRACT] Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR -mutant lung cancers. Here, we modeled disease progression using EGFR -mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS / RAF / MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS , KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR -mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment. Author Summary Targeted therapies are being developed at a rapid pace for various cancers. The data presented here further highlight the notion that, even though colorectal cancers, melanomas, GISTs, and lung cancers share common cell-proliferative signaling cascades, mediators of resistance must be elucidated separately for each disease to design individualized treatment. No recurrent NRAS , KRAS , or MEK1 mutations were detected in 212, 195, or 146 patient samples, respectively, but one tumor simultaneously harbored the mutations as follows: EGFR exon19 deletion, EGFR T790M, and BRAF V600E; another harbored an EGFR exon19 deletion with BRAF G469A. Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR -mutant cells conferred resistance to EGFR TKIs. In stable transfectants with mutant NRAS or BRAF , the combination of erlotinib and an MEK inhibitor significantly inhibited cell growth and reduced the levels of phospho-ERK ( Fig. P1 ) . In the case of BRAF V600E, erlotinib plus vemurafenib had the same effect as an MEK inhibitor. Mutations in KRAS , NRAS , MEK1 , or BRAF now have emerged as mediators of acquired resistance to targeted therapies in a variety of cancers. In colorectal cancers, KRAS mutations are associated with resistance to the anti-EGFR monoclonal antibody cetuximab. In melanomas, NRAS and MEK1 mutations mediate resistance to the inhibitor of mutant BRAF kinase, vemurafenib. In gastrointestinal stromal tumors (GISTs) harboring mutations in genes encoding other members of the protein tyrosine kinase receptor superfamily ( KIT and PDGFRα ), BRAF mutations occur in patients after long-term treatment with imatinib. KRAS mutations are not detected in lung tumors from patients with secondary resistance to EGFR-TKIs ( 2 – 4 ). However, the sample sizes are small ( n = 37, 14, and 6, respectively, in three studies). Only one study examined samples for BRAF mutations; no studies examined MEK1 . Prompted by these data and by the finding that a clinically relevant mouse lung tumor model of acquired resistance to TKIs also identified secondary Kras mutations ( 5 ), we systematically analyzed the frequency of known hotspot mutations in KRAS , NRAS , MEK1 , and BRAF in the largest known collection of samples from patients with acquired TKI resistance. Mechanisms of resistance to TKIs that have been revealed by studies of EGFR -mutant lung adenocarcinomas include second-site resistance EGFR mutations (>50%), amplification of the gene encoding the receptor MET (5–10%), mutations in the gene ( PIK3CA ) encoding the p110α catalytic subunit of the downstream signaling lipid kinase PI3K (<5%), and histologic transformation [i.e., cells display epithelial–mesenchymal transition (EMT) or small cell lung cancer] (<5%) ( 1 , 2 ). Here, to explore other potential modes of drug resistance, we used five TKI-sensitive parental human EGFR -mutant lines to develop six lines with acquired resistance. Five of six cells developed known mechanisms, i.e., an EGFR T790M mutation, MET amplification, or EMT. One cell line (11-18R) displayed an unexpected acquired NRAS Q61K mutation. Resistant cells were sensitive to concurrent treatment with EGFR and MEK inhibitors but to neither drug alone. Consistent with these findings, only the combination of erlotinib and an MEK inhibitor strongly diminished levels of phospho-ERK, a signaling protein that acts downstream of NRAS in the EGFR signaling pathway. Lung cancers with somatic epidermal growth factor receptor ( EGFR ) mutations initially are highly sensitive to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib ( 1 ), but progression of disease (i.e., “acquired” or “secondary” resistance) occurs after about a year. In up to 40% of patients, mechanisms of resistance are unexplained. Here, through analysis of nearly 200 tumor samples for known “hotspot” mutations in genes ( KRAS, NRAS, MEK1, or BRAF ) encoding components of the EGFR signaling pathway ( Fig. P1 ) , we report that mutations in BRAF mediate resistance in 1% of cases. These results provide deeper insights into mechanisms of acquired resistance, inform ongoing clinical trials designed to treat refractory disease, and suggest that, among these genes, only BRAF mutations need be determined routinely in samples from such patients. Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR -mutant lung cancers. Here, we modeled disease progression using EGFR -mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS / RAF / MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS , KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR -mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment. |
| Author | Ladanyi, Marc Pan, Yumei Pao, William Toyooka, Shinichi Vnencak-Jones, Cindy L Arcila, Maria E Fidias, Panos Shien, Kazuhiko Aoe, Keisuke Sequist, Lecia V de Stanchina, Elisa Yang, James Chih-Hsin Kiura, Katsuyuki Kris, Mark G Engelman, Jeffrey A Lin, Ya-Lun Wang, Lu Miller, Vincent A Moran, Teresa Riely, Gregory J Dias-Santagata, Dora Fernandez-Cuesta, Lynnette Chmielecki, Juliann Ohashi, Kadoaki |
| Author_xml | – sequence: 1 fullname: Ohashi, Kadoaki – sequence: 2 fullname: Sequist, Lecia V – sequence: 3 fullname: Arcila, Maria E – sequence: 4 fullname: Moran, Teresa – sequence: 5 fullname: Chmielecki, Juliann – sequence: 6 fullname: Lin, Ya-Lun – sequence: 7 fullname: Pan, Yumei – sequence: 8 fullname: Wang, Lu – sequence: 9 fullname: de Stanchina, Elisa – sequence: 10 fullname: Shien, Kazuhiko – sequence: 11 fullname: Aoe, Keisuke – sequence: 12 fullname: Toyooka, Shinichi – sequence: 13 fullname: Kiura, Katsuyuki – sequence: 14 fullname: Fernandez-Cuesta, Lynnette – sequence: 15 fullname: Fidias, Panos – sequence: 16 fullname: Yang, James Chih-Hsin – sequence: 17 fullname: Miller, Vincent A – sequence: 18 fullname: Riely, Gregory J – sequence: 19 fullname: Kris, Mark G – sequence: 20 fullname: Engelman, Jeffrey A – sequence: 21 fullname: Vnencak-Jones, Cindy L – sequence: 22 fullname: Dias-Santagata, Dora – sequence: 23 fullname: Ladanyi, Marc – sequence: 24 fullname: Pao, William |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/22773810$$D View this record in MEDLINE/PubMed |
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| Notes | http://dx.doi.org/10.1073/pnas.1203530109 Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved May 31, 2012 (received for review March 2, 2012) Author contributions: K.O. and W.P. designed research; K.O., M.E.A., J.C., Y.-L.L., Y.P., L.W., E.d.S., K.S., and L.F.-C. performed research; M.E.A., Y.-L.L., Y.P., C.L.V.-J., D.D.-S., and M.L. contributed new reagents/analytic tools; L.V.S., T.M., K.A., S.T., K.K., L.F.-C., P.F., J.C.-H.Y., V.A.M., G.J.R., M.G.K., and J.A.E. collected patient samples; K.O., L.V.S., M.E.A., T.M., Y.-L.L., Y.P., L.W., K.S., K.A., S.T., K.K., P.F., J.C.-H.Y., V.A.M., G.J.R., M.G.K., J.A.E., C.L.V.-J., D.D.-S., M.L., and W.P. analyzed data; and K.O. and W.P. wrote the paper. |
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| Snippet | Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR -mutant lung cancers. Here, we modeled disease... Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease... Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR -mutant lung cancers. Here, we modeled disease... |
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| SubjectTerms | Amino Acid Substitution Biological Sciences Cell Line, Tumor Cells clinical trials Clinical Trials as Topic colorectal neoplasms Drug Resistance, Neoplasm epidermal growth factor receptors Female gastrointestinal system Gene expression genes Humans Kinases Lung cancer lung neoplasms Lung Neoplasms - drug therapy Lung Neoplasms - enzymology Male MAP Kinase Kinase 1 - genetics MAP Kinase Kinase 1 - metabolism melanoma Metastasis mutants Mutation Mutation, Missense neoplasm cells patients PNAS Plus Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins B-raf - metabolism Proto-Oncogene Proteins p21(ras) ras Proteins - genetics ras Proteins - metabolism Receptor, Epidermal Growth Factor - antagonists & inhibitors Receptor, Epidermal Growth Factor - genetics Receptor, Epidermal Growth Factor - metabolism Tumors tyrosine |
| Title | Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1 |
| URI | http://www.pnas.org/content/109/31/E2127.abstract https://www.ncbi.nlm.nih.gov/pubmed/22773810 https://www.proquest.com/docview/1030716182 https://pubmed.ncbi.nlm.nih.gov/PMC3411967 |
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