Youhong Fan

Podoplanin: A Novel Marker for Oral Cancer Risk in Patients With Oral Premalignancy

PURPOSEnOral leukoplakia (OPL) is a heterogeneous oral lesion with an increased oral cancer risk. Current clinical parameters cannot predict the potential of malignant transformation in patients with OPL. We have shown that podoplanin, a lymphatic endothelial marker, is highly expressed in oral cancer and some oral premalignancies. The purpose of this study is to determine a role of podoplanin in predicting oral cancer development in patients with OPL.nnnPATIENTS AND METHODSnPodoplanin expression was determined in 150 OPL patients with long-term follow-up using immunohistochemistry. Association between the protein expression patterns and clinicopathologic parameters including oral cancer development during the follow-up were analyzed.nnnRESULTSnFifty-six (37%) of the 150 OPL patients exhibited podoplanin expression in the basal and suprabasal layers and were classified as podoplanin positive. Podoplanin positivity was more frequent in older patients (P = .016), females (P = .020), and dysplastic lesions (P = .040). Patients with OPL that was podoplanin positive had significantly higher incidence of oral cancer than did those whose OPL was podoplanin negative (P = .0002). In the multivariate analysis using histology and podoplanin as cofactors, podoplanin was the only independent factor for oral cancer development (hazard ratio = 3.087; 95% CI, 1.530 to 6.231; P = .002). Importantly, oral cancer risk can be further stratified by considering both histology and podoplanin information.nnnCONCLUSIONnPodoplanin is frequently expressed in OPL. Together with histology, podoplanin may serve as a powerful biomarker to predict the risk for oral cancer development in patients with OPL.

ΔNp63 Overexpression, Alone and in Combination with Other Biomarkers, Predicts the Development of Oral Cancer in Patients with Leukoplakia

Purpose: The risk of malignant transformation of oral preneoplastic lesion (OPL) is difficult to assess. ΔNp63 is an early oncoprotein associated with mucosal tumorigenesis. The purpose of this study was to assess ΔNp63 expression in OPL and its role as a marker of oral cancer risk. Experimental Design: ΔNp63 expression was determined using immunohistochemistry in 152 OPL patients included in a clinical trial comparing retinyl palmitate alone or plus β-carotene with low-dose 13-cis-retinoic acid. The associations between ΔNp63 expression as well as ΔNp63 expression with other potential risk factors for oral cancer development were analyzed. Results: ΔNp63 expression was positive in 41 (27%) patients, clusters of intraepithelial inflammatory cells (EIC) were noted in 37 (26%) patients, and podoplanin (previously reported) was positive in 56 (37%) patients. Significantly more patients whose lesions were ΔNp63 positive or exhibited EIC developed oral cancers. In the multicovariate analysis including age, treatment, and histologic status as cofactors, positive ΔNp63 expression was associated with an increased hazard ratio of 3.308 (95% confidence interval, 1.663-6.580; P = 0.0007). Patients whose lesions showed positive ΔNp63, podoplanin, and EIC had the highest oral cancer risk with a hazard ratio of 4.372 (95% confidence interval, 1.912-9.992; P = 0.0005) and 61% oral cancer development rate at 5 years compared with 15% of other OPL patients (P < 0.0001). Conclusion: ΔNp63 overepression in OPL is associated with increased oral cancer risk. Together, ΔNp63, podoplanin, and EIC may be used as biomarkers to identify OPL patients with substantially high oral cancer risk. (Clin Cancer Res 2009;15(19):6284–91)

Abstract 3870: SLFN11 is a biomarker of sensitivity to PARP inhibition and chemotherapy in small cell lung cancer (SCLC)

Small cell lung cancer (SCLC) is an aggressive disease that accounts for 14% of lung cancers. Very little progress has been made towards the treatment of SCLC in the past four decades and there are no established biomarkers to predict effective therapies for patients. In other cancers, SLFN11 plays an important role in sensitizing cancer cells to topoisomerase inhibitors, DNA synthesis inhibitors and alkylating agents. Previously, our lab identified an increase in poly (ADP-Ribose) polymerase 1 (PARP1), an enzyme involved in DNA damage repair, in SCLC patients and cell lines. PARP inhibitors demonstrate significant anti-tumor activity in cell line and animal models of SCLC and are currently being tested in clinical trials for SCLC patients. In Ewing sarcoma (EWS), SLFN11 has been proposed as a biomarker of PARP inhibitor response. Because both EWS and SCLC have high PARP levels and respond favorably to PARP inhibition, we hypothesized that SLFN11 may also be a biomarker for drug sensitivity in SCLC. Using SCLC patient tumors and a large panel of molecularly profiled SCLC cell lines, we investigated the expression of SLFN11 in SCLC and its association with in vitro sensitivity to PARP inhibition (olaparib) and chemotherapy. SLFN11 mRNA levels are significantly higher in SCLC patient tumors relative to normal lung tissue (P = 0.005). In a panel of 51 SCLC cell lines, higher SLFN11 protein expression correlates with both cisplatin (P Citation Format: C. Allison Stewart, Pan Tong, Robert Cardnell, Triparna Sen, Fatemah Mina Masrorpour, Youhong Fan, Jing Wang, Lauren Averett Byers. SLFN11 is a biomarker of sensitivity to PARP inhibition and chemotherapy in small cell lung cancer (SCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3870.

Biomarker-Integrated Neoadjuvant Dasatinib Trial in Resectable Malignant Pleural Mesothelioma

Introduction: Window of opportunity trials in malignant pleural mesothelioma (MPM) are challenging but can yield important translational information about a novel agent. Methods: We treated patients with MPM (N = 24) with 4 weeks of oral dasatinib followed by surgery with or without radiotherapy and then an optional 2 years of maintenance dasatinib. The primary end point was biomarker modulation of phosphorylated (p) SrcTyr419. Results: For all patients, the median progression‐free survival (PFS) was 7.5 months and the median overall survival was 19.1 months. No significant responses were seen after 4 weeks of dasatinib therapy; however, modulation of median p‐SrcTyr419 immunohistochemistry (IHC) scores was seen: the median pretreatment score was 70 (interquartile range 37.5–110), and the median posttreatment score was 41.9 (interquartile range 4.2–60) (p = 0.004). A decrease in p‐SrcTyr419 levels after dasatinib correlated with improved median PFS (6.9 months versus 0.94 months [p = 0.03]), suggesting that p‐SrcTyr419 is a viable pharmacodynamic biomarker for dasatinib in MPM. Platelet‐derived growth factor receptor (PDGFR) pathway analysis correlated high PDGFR beta [PDGFRB) level (in the cytoplasm [hazard ratio] (HR) = 2.54, p = 0.05], stroma [HR = 2.79, p = 0.03], and nucleus [HR = 6.79, p = 0.023]) with a shorter PFS. Low (less than the median) cytoplasmic p‐PDGFR alpha IHC levels were predictive of a decrease in positron emission tomography/computed tomography standard uptake values levels after dasatinib therapy (p = 0.04), whereas higher‐than‐median IHC scores of PDGFRB (cytoplasmic [HR = 2.8, p = 0.03] and nuclear [HR = 6.795, p = 0.02]) were correlated with rising standard uptake values levels. Conclusions: In conclusion, there was no significant efficacy signal, and dasatinib monotherapy will not continue to be studied in MPM. However, our study demonstrated that PDGFR subtypes (platelet‐derived growth factor receptor alpha and PDGFRB) may have differential roles in prognosis and resistance to antiangiogenic tyrosine kinase inhibitors and are important potential therapeutic targets that require further investigation.

Abstract 3623: Neoadjuvant chemotherapy is associated with increased expression of DNA repair proteins and epithelial to mesenchymal transition (EMT) in patients with non-small cell lung cancer (NSCLC)

Background: Proteomic profiling has elucidated several dysregulated pathways in NSCLC. We sought to identify patterns of protein expression that are enriched following neoadjuvant chemotherapy in patients with resected lung cancers. Methods: Tissue samples were selected from the PROSPECT trial at MD Anderson Cancer Center, the goal of which was to correlate molecular profiles with treatment response. Samples from 189 patients were analyzed, which included 26% squamous tumors; 27% with neoadjuvant chemotherapy (n = 49); and predominantly localized disease (distribution: I = 91, II = 35, III = 58, IV = 5). Reverse phase protein array (RPPA) analysis was utilized to quantify 127 total or phosphorylated proteins. Interactions between protein expression and the receipt of neoadjuvant chemotherapy were assessed by analysis of variance (ANOVA). Cox regression was performed to determine the relationship between protein expression and recurrence-free survival (RFS). Results: Twenty one of the 127 proteins (16%) were expressed at significantly different levels in patients receiving neoadjuvant chemotherapy. Specifically, patients receiving neoadjuvant chemotherapy had higher expression of multiple DNA repair proteins, including MSH2 (p Conclusions: The receipt of neoadjuvant chemotherapy was associated with higher expression of DNA repair proteins, suppression of the PI3K pathway, and an EMT shift. Increased expression of DNA repair proteins was also associated with reduced RFS. These findings suggest that higher expression of DNA repair proteins may contribute to treatment resistance, and support the combination of standard chemotherapy with targeted agents such as Chk inhibitors or immunotherapy (to address EMT-mediated immune escape). Citation Format: Daniel R. Gomez, Lixia Diao, Jing Wang, Ignacio I. Wistuba, Cesar Moran, Neda Kalhor, Milind B. Suraokar, Stephen G. Swisher, Carmen Behrens, Youhong Fan, John V. Heymach, Lauren A. Byers. Neoadjuvant chemotherapy is associated with increased expression of DNA repair proteins and epithelial to mesenchymal transition (EMT) in patients with non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3623. doi:10.1158/1538-7445.AM2015-3623

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.nnMethods: 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.nnResults: 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.nnConclusion: 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.nnCitation Information: Mol Cancer Ther 2013;12(11 Suppl):C117.nnCitation 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.

Abstract 567: CD38 blockade overcomes the immune resistance to anti-PD-L1 therapy by boosting CD8 T cell response

Although strategies incorporating immune checkpoint inhibition, e.g. PD-1/PD-L1 blockade, are achieving unprecedented successes and increasingly becoming incorporated into standard of care regimens for cancer patients, high rates of resistance still limit the potential efficacy. Therapeutic improvement requires a thorough understanding of the biological process of resistance. To date there have been few studies reporting mechanisms of resistance to PD-L1 blockade. We have explored the resistance mechanisms to functional PD-L1 loss in preclinical lung cancer models by using pharmacological and genetic approaches (PD-L1 blocking antibody treatment or CRISPR/Cas9-mediated deletion of PD-L1 on tumor cells). The molecular and immune profiles of the tumor microenvironment were evaluated in mutant K-ras/p53 (KP) GEM lung cancer models and multiple immunocompetent syngeneic models (both KP and Lewis lung cancer). Additionally, to determine the applicability of the results to patients with lung cancer, we analyzed 259 patient tumor specimens with IHC staining and evaluated the immune markers in TCGA datasets (adenocarcinoma and squamous) and the MD Anderson PROSPECT dataset. We observed that lung tumors gained resistance to anti-PD-L1 antibody treatment over time, and that the up-regulation of CD38 on tumor cells accounted for the treatment resistance. We also observed the same resistance mechanism caused by CD38 up-regulation in PD-L1 KO mice bearing PD-L1 KO Lewis lung tumors generated with the CRISPR/Cas9 system. Manipulation of CD38 on a panel of lung cancer cell lines, demonstrated that CD38 inhibits CD8+ T cell proliferation, antitumor cytokine secretion, and tumor cell killing capability in vitro and in vivo. Furthermore, to test whether CD38 blockade might be therapeutically efficacious to counter anti-PD-L1 resistance, we applied the combination therapy of anti-CD38 and anti-PD-L1 in lung cancer animal models and demonstrated dramatic therapeutic benefit on primary tumor growth and metastasis. Bioinformatic analyses of the patient tumor databases revealed a strong correlation between CD38 expression and an immune suppressive inflammatory signature. Finally, in 259 lung cancer specimens, 18.5% of cases exhibited positive staining for CD38 on tumor cells. Based upon our studies, we conclude that the up-regulation of CD38 on tumor cells is a major mechanism of resistance to anti-PD-L1 therapy, and that CD38 is a novel immune checkpoint that inhibits CD8+ T cell function. The blockade of CD38 and PD-L1 is a rational combination to prevent immune resistance and increase the response rate for lung cancer patients. Citation Format: Limo Chen, Lixia Diao, Yongbin Yang, Xiaohui Yi, Jaime Rodriguez, Youhong Fan, Leticia Rodriguez, Jared Fradette, Christin Ungewiss, Jonothan Roybal, Jingfen Zhu, Jing Wang, Lauren Byers, Stephen Ullrich, Ignacio Wistuba, John Heymach, Xiao-Feng Qin, Don Gibbons. CD38 blockade overcomes the immune resistance to anti-PD-L1 therapy by boosting CD8 T cell response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 567. doi:10.1158/1538-7445.AM2017-567

Abstract 4662: Beta blockers abrogate EGFR TKI resistance induced by adrenergic receptor-mediated upregulation of IL-6 and modulation of the LKB1/AMPK/mTOR axis

Therapeutic strategies to target EGFR tyrosine kinase inhibitor (TKI) resistance mediated by mechanisms other than T790M are a major clinical challenge. Studies have implicated IL-6 as a mediator of EGFR TKI resistance, and IL-6 is known to be regulated by adrenergic receptors (AR) in some cancers. We investigated whether adrenergic pathways can promote T790M-independent EGFR TKI resistance in preclinical models and in clinical studies. We found that β2-AR was highly expressed in our panel of 119 cell lines and in NSCLC clinical specimens. Activation of β-ARs by stress hormones such as norepinephrine (NE) induced a dramatic rise in IL-6, and this occurred through β2-ARs. β-AR inhibitors (i.e. propranolol), but not α-AR inhibitors, blocked IL-6 induction. Analysis of downstream signaling pathways revealed that β2-ARs induced IL-6 expression through activation of adenylyl cyclase, p90RSK and CREB. To identify novel signaling pathways modulated by ARs, we stimulated NSCLC cell lines with NE and analyzed protein lysates by RPPA to detect expression and activation of >100 proteins. β-AR signaling inactivated the tumor suppressor LKB1 through phosphorylation of S428 and subsequently increased mTOR activity. LKB1 inactivation was critical for IL-6 induction. This finding is important as LKB1 loss is known to be a driver of NSCLC resistance and metastasis. Moreover, we found that β2-AR activation promoted EGFR TKI resistance in cell lines and in mouse models of EGFR mutant NSCLC. The effect of β-AR on EGFR TKI resistance was blocked by the addition of the beta blocker propranolol or IL-6 antibodies, in vitro and in vivo. Consistent with our preclinical studies, in the phase III ZEST clinical study testing erlotinib vs vandetanib, we found that high plasma levels of IL-6 was associated with a worse PFS and OS in the erlotinib arm. In addition, we found that circulating levels of IL-6 were significantly lower in NSCLC patients incidentally receiving beta blockers in the BATTLE trial. Finally, we analyzed the influence of incidental beta blocker use in the LUX-Lung3 study testing afatinib vs chemotherapy in EGFR mutant NSCLC patients. In patients not receiving beta blockers, the median PFS was 11.1 and 6.9 months for afatinib and chemotherapy, respectively, and afatinib improved PFS with a hazard ratio (HR) of 0.60. In patients receiving beta blockers, the median PFS was 13.6 and 2.5 for afatinib and chemotherapy, respectively, and afatinib improved PFS with a HR of 0.25. In conclusion, our preclinical and clinical data provide evidence that β2-AR activation can upregulate IL-6 in EGFR mutant+ NSCLC, modulate the LKB1/AMPK/mTOR axis, and promote EGFR TKI resistance. Moreover, EGFR mutant+ patients using beta blockers had greater relative PFS benefit from afatinib vs chemotherapy compared with those not using beta blockers, supporting future clinical testing of EGFR TKIs in combination with beta blockers. Citation Format: Monique B. Nilsson, Huiying Sun, Lixia Diao, Pan Tong, Youhong Fan, Hai Tran, Diane Liu, Guillermo Armaiz Pena, Jing Wang, Phil Rowe, Alan Webster, Jack Lee, Daniel Gomez, Waun Ki Hong, Ignacio Wistuba, Anil Sood, John Heymach. Beta blockers abrogate EGFR TKI resistance induced by adrenergic receptor-mediated upregulation of IL-6 and modulation of the LKB1/AMPK/mTOR axis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4662.

Abstract 3364: Epithelial-mesenchymal transition is associated with a profound inflammatory tumor microenvironment in lung adenocarcinoma

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAnnPromising results in the treatment of non-small cell lung cancer (NSCLC) have been seen with immunomodulatory agents targeting immune checkpoints, such as programmed cell death 1 (PD-1) or programmed cell death 1 ligand (PD-L1). However, only a select group of patients respond to these interventions. The identification of biomarkers that predict clinical benefit to immune-based approaches, such as immune checkpoint blockade, is critical to successful translation of these agents. By using integrated gene array analysis in three large independent NSCLC patient datasets along with immunohistochemistry study (IHC), reverse phase protein array (RPPA) and in vivo animal study, we demonstrated that epithelial-mesenchymal transition (EMT) is highly associated with a profound inflammatory tumor microenvironment in lung adenocarcinoma. Our data revealed immune activation and simultaneous development of multiple immune suppressive mechanisms, including elevation of immune checkpoints such as PD-L1, PD-L2, PD-1, TIM-3, BTLA and CTLA-4, as well as an increase in tumor infiltrating CD4+Foxp3+ regulatory T cells, IL-6 and indoleamine 2,3-dioxygenase (IDO) in lung adenocarcinomas with a mesenchymal phenotype. Our data suggested that EMT might represent a potential biomarker to select the patients who will benefit from immune checkpoint blockade agents and other immunotherapies in NSCLC and possibly other cancers.nnNote: This abstract was not presented at the meeting.nnCitation Format: Yanyan Lou, Lixia Diao, Parra Cuentas Edwin Roger, Warren L. Denning, Limo Chen, Youhong Fan, Jaime Rodriguez, Lauren Byers, Jing Wang, Vassiliki Papadimitrakopoulou, Behrens Carmen, Ignacio I. Wistuba, Patrick Hwu, John V. Heymach, Don L. Gibbons. Epithelial-mesenchymal transition is associated with a profound inflammatory tumor microenvironment in lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3364. doi:10.1158/1538-7445.AM2015-3364

Abstract 1040: An integrated analysis of EMT across diverse cancer types identifies new potential therapeutic targets

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAnnBackground: Epithelial-to-mesenchymal transition (EMT) is a marker of resistance to specific targeted drugs in non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSC), and other epithelial cancer and may be associated with poor patient outcomes. Here we performed an integrated molecular analysis in 1934 tumors representing 11 different cancer types in the Cancer Genome Atlas (TCGA) and 1264 representative cell lines to investigate new potential therapeutic targets (PTTs) in mesenchymal tumors.nnMethods: For each tumor, we correlated the EMT score (based on expression of an EMT gene signature) with mutation status, copy number alterations (CNA), mRNA, miRNA, and protein expression. PTTs expressed in mesenchymal tumors were investigated in vitro using publically available drug sensitivity datasets (DSDs) by correlating IC50s with EMT score.nnResults: Most cancer types exhibited a range of EMT scores that included both epithelial and mesenchymal tumors, with the exception of kidney clear cell carcinoma (KIRC) (all mesenchymal) and ovarian serous cystadenocarcinoma (OV) (primarily epithelial). Patients with mesenchymal OV and HNSC experienced shorter overall survival (p=0.029 and 0.076, respectively). BAP1 and PP2R1A mutations were more frequent in mesenchymal tumors, independent of primary site (adjusted p value 0.3). PTTs commonly expressed in mesenchymal tumors included AXL, PDGFRA/B, MMP2 and DDR2 (r>0.6). Of these, investigation of the DSDs supported in vitro sensitivity of mesenchymal cell lines overall to PDGFR and GSK3 inhibitors, but resistance to drugs targeting ErbB family members, including the dual VEGF/EGFR inhibitor vandetanib (p<0.001) and drugs targeting Her2 and/or EGFR (p<0.001). In contrast, other EMT-associated drug resistance was tissue specific, such as resistance of mesenchymal breast cancer lines to mTOR inhibition (p 0.03).nnConclusions: Application of the EMT signature to diverse tumor types identifies highly conserved patterns of gene and miRs expression, including high miR-199a expression in mesenchymal cancers. While mutational landscape and CNAs were most often driven by tumor type, protein expression and drug sensitivity were influenced by a combination of tumor type and EMT status. New associations between drug response and EMT were identified, such as the sensitivity of mesenchymal cancers to PDGFR and GSK3 inhibitors, that warrant further investigation.nnCitation Format: Pan Tong, Milena P. Mak, Lixia Diao, Jing Wang, Patrick Kwok-Shing Ng, You-hong Fan, William N. William, John V. Heymach, Kevin R. Coombes, Lauren Averett Byers. An integrated analysis of EMT across diverse cancer types identifies new potential therapeutic targets. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1040. doi:10.1158/1538-7445.AM2014-1040