Erlotinib resistance in mouse models of epidermal growth factor receptor-induced lung adenocarcinoma

Politi, Katerina; Fan, Pang-Dian; Shen, Ronglai; Zakowski, Maureen F.; Varmus, Harold

doi:10.1242/dmm.003681

Cited by 78 publications

(88 citation statements)

References 21 publications

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“…Cells were grown in a humidified incubator with 5% CO 2 at 37°C. To create EGFR TKIresistant lines, parental cells were cultured with increasing concentrations of TKIs starting with the IC 30 . Doses were increased in a stepwise pattern when normal cell proliferation patterns resumed.…”

Section: Methodsmentioning

confidence: 99%

“…Given the RAS-related findings in the murine (30) and cell-line models of acquired resistance and the reported data regarding KRAS/NRAS/BRAF/MEK1 mutations in other cancers that grow after responding to targeted therapies (25-28), we reexamined the frequency of mutations occurring in KRAS, NRAS, BRAF, and MEK1 in 195, 212, 195, and 146 tumor samples, respectively, from patients with acquired resistance to EGFR TKIs. Tumors were screened by a variety of methods including a SNapShot/sizing platform (32,38), a Sequenom mass spectrometrybased assay (39), and/or direct sequencing.…”

Section: Ras Signaling Pathway Gene Mutations In Tumors From Patientsmentioning

confidence: 99%

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Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1

Ohashi

Sequist

Arcila³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

407

333

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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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Section: Methodsmentioning

confidence: 99%

Section: Ras Signaling Pathway Gene Mutations In Tumors From Patientsmentioning

confidence: 99%

Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1

Ohashi

Sequist

Arcila³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

407

333

View full text Add to dashboard Cite

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“…To simulate tumor subclonal heterogeneity and contamination with infiltrating nontumor stromal cells, we serially diluted the 129S1/ SvImJ library (mimicking "tumor DNA") into the C57BL/6 library (10). Tumors were collected from untreated tumor-bearing mice, or mice were treated with erlotinib as described until the appearance of resistant tumors (12). Untreated and erlotinibresistant lung tumors were collected and used for exome sequencing.…”

Section: Mouse Models Of Lung Adenocarcinoma Acquire Few Somatic Pointmentioning

confidence: 99%

Mutational landscape of EGFR- , MYC- , and Kras- driven genetically engineered mouse models of lung adenocarcinoma

McFadden

Politi

Bhutkar

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

169

112

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Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC protooncogene. Tumors from EGFR-and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR-and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

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“…Thus, GEMMs, with their ability to mimic therapeutic resistance in toto and increased tumor tissue accessibility, could provide an invaluable means to model therapeutic response, refractory patient populations, and the dynamic evolution of tumors on treatment. An excellent example of GEMMs applied in this fashion is found in the work of Politi and colleagues (45), who showed that mouse models of mutant EGFR-driven lung carcinomas give rise to drug-resistant tumors that exhibit the same molecular changes that confer resistance in human lung cancers when treated with the tyrosine kinase inhibitor erlotinib. Similarly, GEMMs have been successfully used to model acquired resistance to chemotherapy and have provided key insights into the underlying mechanisms and cell types involved.…”

Section: Introductionmentioning

confidence: 99%

Genetically Engineered Mouse Models: Closing the Gap between Preclinical Data and Trial Outcomes

Singh¹,

Murriel²,

Johnson³

2012

Cancer Research

117

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The high failure rate of late-stage human clinical trials, particularly in oncology, predicates the need for improved translation of preclinical data from mouse tumor models into clinical predictions. Genetically engineered mouse models (GEMM) may fulfill this need, because they mimic spontaneous and autochthonous disease progression. Using oncogenic Kras-driven GEMMs of lung and pancreatic adenocarcinoma, we recently showed that these models can closely phenocopy human therapeutic responses to standard-of-care treatment regimens. Here we review the successful preclinical application of such GEMMs, as well as the potential for discovering predictive biomarkers and gaining mechanistic insights into clinical outcomes and drug resistance in human cancers. Cancer Res; 72(11); 2695-700. Ó2012 AACR.

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Erlotinib resistance in mouse models of epidermal growth factor receptor-induced lung adenocarcinoma

Cited by 78 publications

References 21 publications

Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1

Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1

Mutational landscape of EGFR- , MYC- , and Kras- driven genetically engineered mouse models of lung adenocarcinoma

Genetically Engineered Mouse Models: Closing the Gap between Preclinical Data and Trial Outcomes

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