Abstract C117: An integrated proteomic analysis of lung adenocarcinomas from The Cancer Genome Atlas (TCGA) reveals potential targets for oncogene-negative tumors.

Background: The discovery of driver genes such as EGFR, ALK, and ROS1 in non-small cell lung cancer has led to novel, highly active therapies for a subset of patients. However, the majority of lung adenocarcinomas do not have alterations in established driver oncogenes. Here we used an integrated proteomic and genomic analysis of the Cancer Genome Atlas (TCGA) to identify potential therapeutic targets in oncogene-negative lung adenocarcinomas. Methods: Protein expression was measured by reverse phase protein array in 181 TCGA lung adenocarcinoma tumors. Protein levels were correlated with mutational status by t-test for individual mutations and for oncogene-positive versus negative tumors. A false discovery rate of 0.10 (corresponding p-value ≤0.047) was used for these analyses. Results: Expression of 160 total and phospho-proteins were compared between oncogene-positive and negative tumors using reverse phase protein array (RPPA). Oncogene-positive tumors included those with canonical mutations in KRAS, EGFR, BRAF, ROS1, ALK, RET, MAPK1, HRAS, NRAS, AKT1, MET, or ERBB2. For the two most frequent driver oncogenes, KRAS (n=47) and EGFR (n=27), the top markers expressed in mutated tumors were pRaf/pMAPK/pERK (KRAS mutated) and pEGFR (EGFR mutated) (p<0.0001 for all). In contrast, oncogene-negative tumors had higher levels of protein markers associated with apoptosis, DNA repair, and cell cycle. Among those overexpressed in oncogene-negative tumors, potentially targetable proteins included total and phosphorylated Chk1 (p=0.01 and p<0.0001, respectively), total and pChk2 (p=0.017 and 0.002), and Bim (p<0.0001). Thymidylate synthase, a marker previously associated with pemetrexed resistance, was also more highly expressed in oncogene-negative tumors (p<0.0001). KEAP1, a regulator of oxidative stress response, was the second most commonly mutated gene in oncogene-negative tumors (after TP53). KEAP1 mutated tumors expressed lower protein levels of KEAP1 (p<0.0001) and higher NRF2 (p<0.001) (normally targeted by KEAP1 for degradation), as well as lower levels of pAMPK and pNFKB (P<0.0001 and 0.006, respectively). Finally, KEAP1 mutated tumors were also frequently negative for expression of TTF1 (p=0.001, fisher test), a transcription factor commonly used as a histological marker in the diagnosis of lung adenocarcinoma. In comparison, oncogene-positive tumors (especially EGFR and BRAF mutated adenocarcinomas) expressed high levels of TTF1. Conclusion: Potentially targetable or predictive markers, including Chk1/2, Bim, and thymidylate synthase, were expressed at higher levels in oncogene-negative lung adenocarcinomas. These findings support further investigation of these targets and associated biomarkers and could provide a treatment strategy for patients without established driver mutations such as EGFR, ALK, and ROS1. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C117. Citation Format: Lixia Diao, Pan Tong, Jing Wang, You-Hong Fan, Yiling Lu, Wenbin Liu, Carmen Behrens, Ignacio I. Wistuba, John V. Heymach, John N. Weinstein, Gordon B. Mills, Lauren A. Byers. An integrated proteomic analysis of lung adenocarcinomas from The Cancer Genome Atlas (TCGA) reveals potential targets for oncogene-negative tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C117.