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Clinical Research

Abstract 5040: Dysregulation of the mTOR/AKT pathway in serum tumor DNA correlates with primary and acquired resistances to erlotinib in advanced NSCLC patients

Sonal J. Desai, Yi-He Ling, Ryan Davis, Clifford G. Tepper, David R. Gandara, Roman Perez-Soler and Tianhong Li
Sonal J. Desai
1University of California – Davis, Sacramento, CA
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Yi-He Ling
2Albert Einstein College of Medicine, Bronx, NY
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Ryan Davis
1University of California – Davis, Sacramento, CA
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Clifford G. Tepper
1University of California – Davis, Sacramento, CA
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David R. Gandara
1University of California – Davis, Sacramento, CA
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Roman Perez-Soler
3Montefiore Medical Center, Bronx, NY.
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Tianhong Li
1University of California – Davis, Sacramento, CA
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DOI: 10.1158/1538-7445.AM2011-5040 Published April 2011
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Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL

Abstract

Non-small cell lung cancer (NSCLC) is the most common and lethal cancer worldwide. Erlotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is the first molecularly targeted agent that has demonstrated modest yet comparable survival benefit to chemotherapy in unselected patients with advanced NSCLC after failing first-line chemotherapy. However, all patients eventually die from disease progression and a cure does not currently exist, even in patients with NSCLC tumors harboring EGFR TKI-sensitive EGFR mutations and achieving an initially dramatic tumor response. We previously demonstrated that dysregulation of the EGFR/mTOR/AKT signaling pathway contributes primarily to the acquired resistance to erlotinib in an erlotinib-resistant clone H3255R#2 (EGFRWT/WT), which was derived from the parental, erlotinib-sensitive human lung adenocarcinoma cell line H3255 (EGFRL858R/WT). To gain further molecular insights into the resistance mechanisms, we explored genome-wide alterations in genomic DNA (gDNA) from erlotinib-resistant cells as compared to parental cells using the Affymetrix Human SNP 6.0 array platform, which contains approximately one million probes for the detection of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). We found that significant alterations were simultaneously present in several core functional pathways, including ErbB, mTOR/AKT, apoptosis, and cell cycle, as well as EMT, stem cell and metastasis related genes. Selected targets have been validated in vitro. Serum tumor DNA has emerged as an easily accessible and stable source of tumor biospecimens for advanced NSCLC patients and has been used for detecting somatic mutations in EGFR and K-Ras genes either directly or amplified by high fidelity whole genome amplification technology. We further determined whether this genome-wide array-based platform could be used to clinically assess the drug resistance mechanisms in advanced NSCLC patients. We analyzed the genomic alterations in two paired serum tumor DNA samples obtained before treatment and at treatment failure from NSCLC patients with primary or secondary resistance to erlotinib on a clinical trial (clinicaltrials.gov, identifier: NCT00950365). Of particular interest, we found that there were similar changes in the gDNAs from erlotinib-resistant patients’ sera and gDNA from R#2 cells within the mTOR/AKT pathway, including amplification of PI3K, AMPK, and VEGF genes, and deletion of RSK genes. Analyses on more banked, paired serum tumor DNA samples from patients enrolled in the same trial are ongoing. Our results support targeting the mTOR/AKT and/or VEGF pathway as a strategy to overcome clinical resistance to EGFR TKIs and serum tumor DNA could be a useful surrogate to assessing resistance mechanisms to therapy in advanced NSCLC patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5040. doi:10.1158/1538-7445.AM2011-5040

  • ©2011 American Association for Cancer Research
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Cancer Research: 71 (8 Supplement)
April 2011
Volume 71, Issue 8 Supplement
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Abstract 5040: Dysregulation of the mTOR/AKT pathway in serum tumor DNA correlates with primary and acquired resistances to erlotinib in advanced NSCLC patients
Sonal J. Desai, Yi-He Ling, Ryan Davis, Clifford G. Tepper, David R. Gandara, Roman Perez-Soler and Tianhong Li
Cancer Res April 15 2011 (71) (8 Supplement) 5040; DOI: 10.1158/1538-7445.AM2011-5040

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Abstract 5040: Dysregulation of the mTOR/AKT pathway in serum tumor DNA correlates with primary and acquired resistances to erlotinib in advanced NSCLC patients
Sonal J. Desai, Yi-He Ling, Ryan Davis, Clifford G. Tepper, David R. Gandara, Roman Perez-Soler and Tianhong Li
Cancer Res April 15 2011 (71) (8 Supplement) 5040; DOI: 10.1158/1538-7445.AM2011-5040
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