Julián Carretero

Universitat de València

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Co-Authors

Kwok‐Kin Wong

Dana-Farber Cancer Institute

183

Takeshi Shimamura

University of Illinois Chicago

105

Pasi A. Jänne

Dana-Farber Cancer Institute

Fátima Al‐Shahrour

Spanish National Cancer Research Centre

Margaret Soucheray

Quantitative BioSciences

Geoffrey I. Shapiro

Brigham and Women's Hospital

Jeremy H. Tchaicha

Weatherford College

Montse Sánchez‐Céspedes

Josep Carreras Leukaemia Research Institute

Travis J. Cohoon

University of California, Irvine

Danan Li

Dana-Farber Cancer Institute

Cooperative Institutions

Harvard University

156

Dana-Farber Cancer Institute

127

Universitat de València

Brigham and Women's Hospital

Instituto de Salud Carlos III

Centro de Investigación Biomédica en Red

Dana-Farber/Harvard Cancer Center

INCLIVA Health Research Institute

Massachusetts General Hospital

Broad Institute

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Supplementary Table S3 from Genomic Profiling of Patient-Derived Xenografts for Lung Cancer Identifies B2M Inactivation Impairing Immunorecognition

Carolina Pereira Pol Giménez‐Xavier Eva Pros María J. Pajares Massimo Moro

Supplementary Table S3

Profiling (computer programming)

Table (database)

10.1158/1078-0432.22463657

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Data from Ganetespib (STA-9090), a Nongeldanamycin HSP90 Inhibitor, Has Potent Antitumor Activity in In Vitro and In Vivo Models of Non–Small Cell Lung Cancer

Takeshi Shimamura Samanthi A. Perera Kevin P. Foley Jim Sang Scott J. Rodig

<div>AbstractPurpose: We describe the anticancer activity of ganetespib, a novel non-geldanamycin heat shock protein 90 (HSP90) inhibitor, in non-small cell lung cancer (NSCLC) models.Experimental Design: The activity of ganetespib was compared with that of the geldanamycin 17-AAG in biochemical assays, cell lines, and xenografts, and evaluated in an ERBB2 YVMA-driven mouse lung adenocarcinoma model.Results: Ganetespib blocked the ability of HSP90 to bind to biotinylated geldanamycin and disrupted the association of HSP90 with its cochaperone, p23, more potently than 17-AAG. In genomically defined NSCLC cell lines, ganetespib caused depletion of receptor tyrosine kinases, extinguishing of downstream signaling, inhibition of proliferation and induction of apoptosis with IC50 values ranging 2 to 30 nmol/L, substantially lower than those required for 17-AAG (20–3,500 nmol/L). Ganetespib was also approximately 20-fold more potent in isogenic Ba/F3 pro-B cells rendered IL-3 independent by expression of EGFR and ERBB2 mutants. In mice bearing NCI-H1975 (EGFR L858R/T790M) xenografts, ganetespib was rapidly eliminated from plasma and normal tissues but was maintained in tumor with t1/2 58.3 hours, supporting once-weekly dosing experiments, in which ganetespib produced greater tumor growth inhibition than 17-AAG. However, after a single dose, reexpression of mutant EGFR occurred by 72 hours, correlating with reversal of antiproliferative and proapoptotic effects. Consecutive day dosing resulted in xenograft regressions, accompanied by more sustained pharmacodynamic effects. Ganetespib also showed activity against mouse lung adenocarcinomas driven by oncogenic ERBB2 YVMA.Conclusions: Ganetespib has greater potency than 17-AAG and potential efficacy against several NSCLC subsets, including those harboring EGFR or ERBB2 mutation. Clin Cancer Res; 18(18); 4973–85. ©2012 AACR.</div>

Geldanamycin

Hsp90 inhibitor

T790M

10.1158/1078-0432.c.6519806.v1

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Data from PARD3 Inactivation in Lung Squamous Cell Carcinomas Impairs STAT3 and Promotes Malignant Invasion

Ester Bonastre Sara Verdura Ilse Zondervan Federica Facchinetti Sylvie Lantuéjoul

<div>AbstractCorrect apicobasal polarization and intercellular adhesions are essential for the appropriate development of normal epithelia. Here, we investigated the contribution of the cell polarity regulator PARD3 to the development of lung squamous cell carcinomas (LSCC). Tumor-specific PARD3 alterations were found in 8% of LSCCs examined, placing PARD3 among the most common tumor suppressor genes in this malignancy. Most PAR3-mutant proteins exhibited a relative reduction in the ability to mediate formation of tight junctions and actin-based protrusions, bind atypical protein kinase C, activate RAC1, and activate STAT3 at cell confluence. Thus, PARD3 alterations prevented the formation of contacts between neighboring cells and the subsequent downstream signaling. Notably, reconstituting PAR3 activity in vivo reduced tumor-invasive and metastatic properties. Our findings define PARD3 as a recurrently inactivated cell polarity regulator in LSCC that affects tumor aggressiveness and metastasis. Cancer Res; 75(7); 1287–97. ©2015 AACR.</div>

Cell polarity

10.1158/0008-5472.c.6507201

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Supplementary Figures 1 - 8 from PARD3 Inactivation in Lung Squamous Cell Carcinomas Impairs STAT3 and Promotes Malignant Invasion

Ester Bonastre Sara Verdura Ilse Zondervan Federica Facchinetti Sylvie Lantuéjoul

Figure S1. PARD3-inactivation in the H157 lung cancer cell line. Figure S2. Ratio charts of the multiplex ligation-dependent probe amplification (MLPA) depicting a large intragenic deletion (from exon 4 to 23) in one of the LSCCs but not a normal DNA. Figure S3. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) to determine the presence of promoter hypermethylation of PARD3. Figure S4. Relative abundance of the PARD3 transcriptsFigure S5. Western blot showing ectopic and transient expression of the indicated PAR3 proteins in the H157 cell line, immunoblotted with HA or PAR3 antibodies. Figure S6. Immunofluorescence with the anti-PAR3 antibody in the indicated T98G-derived cells, after (Dox+) induction of PAR3 expression with doxycycline (1 ng/µl, 24h). Scale bar, 50 µm. Figure S7. Western blot depicts the endogenous PAR3 protein in the indicated lung cancer cells and the ectopic expression of PAR3 in the H157tr-pD41_R74del cells (dox, 1 ng/µl; 24 h). Figure S8. Immunostaining of PAR3 in lung primary tumors and head and neck squamous cell carcinomas (HNSCCs).

Ectopic expression

10.1158/0008-5472.22406967

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Data from CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC

Jeffrey H. Becker Yandi Gao Margaret Soucheray Inés Pulido Eiki Kikuchi

<div>AbstractAlthough EGFR mutant–selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK–ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI–resistant persister cells. Many patients with non–small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutation, who progressed on EGFR inhibitors, demonstrated increased CXCR7 expression. These data suggest that CXCR7 inhibition could considerably delay and prevent the emergence of acquired EGFR TKI resistance in EGFR-mutant NSCLC.Significance:Increased expression of the chemokine receptor CXCR7 constitutes a mechanism of resistance to EGFR TKI in patients with non–small cell lung cancer through reactivation of ERK signaling.</div>

EGFR Inhibitors

10.1158/0008-5472.c.6510909.v1

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Supplementary Figures S1-S6 from CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC

Jeffrey H. Becker Yandi Gao Margaret Soucheray Inés Pulido Eiki Kikuchi

Supplementary Figures

10.1158/0008-5472.22421370

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Data from Intratumoral Heterogeneity in EGFR-Mutant NSCLC Results in Divergent Resistance Mechanisms in Response to EGFR Tyrosine Kinase Inhibition

Margaret Soucheray Marzia Capelletti Inés Pulido Yanan Kuang Cloud P. Paweletz

<div>AbstractNon–small cell lung cancers (NSCLC) that have developed resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI), including gefitinib and erlotinib, are clinically linked to an epithelial-to-mesenchymal transition (EMT) phenotype. Here, we examined whether modulating EMT maintains the responsiveness of EGFR-mutated NSCLCs to EGFR TKI therapy. Using human NSCLC cell lines harboring mutated EGFR and a transgenic mouse model of lung cancer driven by mutant EGFR (EGFR-Del19-T790M), we demonstrate that EGFR inhibition induces TGFβ secretion followed by SMAD pathway activation, an event that promotes EMT. Chronic exposure of EGFR-mutated NSCLC cells to TGFβ was sufficient to induce EMT and resistance to EGFR TKI treatment. Furthermore, NSCLC HCC4006 cells with acquired resistance to gefitinib were characterized by a mesenchymal phenotype and displayed a higher prevalence of the EGFR T790M mutated allele. Notably, combined inhibition of EGFR and the TGFβ receptor in HCC4006 cells prevented EMT but was not sufficient to prevent acquired gefitinib resistance because of an increased emergence of the EGFR T790M allele compared with cells treated with gefitinib alone. Conversely, another independent NSCLC cell line, PC9, reproducibly developed EGFR T790M mutations as the primary mechanism underlying EGFR TKI resistance, even though the prevalence of the mutant allele was lower than that in HCC4006 cells. Thus, our findings underscore heterogeneity within NSCLC cells lines harboring EGFR kinase domain mutations that give rise to divergent resistance mechanisms in response to treatment and anticipate the complexity of EMT suppression as a therapeutic strategy. Cancer Res; 75(20); 4372–83. ©2015 AACR.</div>

Acquired resistance

EGFR Inhibitors

10.1158/0008-5472.c.6506858

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Data from Novel Transcriptional Targets of the SRY-HMG Box Transcription Factor SOX4 Link Its Expression to the Development of Small Cell Lung Cancer

Sandra Castillo Ander Matheu Niccolò Mariani Julián Carretero Fernando López‐Ríos

<div>AbstractThe HMG box transcription factor SOX4 involved in neuronal development is amplified and overexpressed in a subset of lung cancers, suggesting that it may be a driver oncogene. In this study, we sought to develop this hypothesis including by defining targets of SOX4 that may mediate its involvement in lung cancer. Ablating SOX4 expression in SOX4-amplified lung cancer cells revealed a gene expression signature that included genes involved in neuronal development such as PCDHB, MYB, RBP1, and TEAD2. Direct recruitment of SOX4 to gene promoters was associated with their upregulation upon ectopic overexpression of SOX4. We confirmed upregulation of the SOX4 expression signature in a panel of primary lung tumors, validating their specific response by a comparison using embryonic fibroblasts from Sox4-deficient mice. Interestingly, we found that small cell lung cancer (SCLC), a subtype of lung cancer with neuroendocrine characteristics, was generally characterized by high levels of SOX2, SOX4, and SOX11 along with the SOX4-specific gene expression signature identified. Taken together, our findings identify a functional role for SOX genes in SCLC, particularly for SOX4 and several novel targets defined in this study. Cancer Res; 72(1); 176–86. ©2011 AACR.</div>

Testis determining factor

SOX4

10.1158/0008-5472.c.6503420.v1

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Supplementary Figures 1-3 from Novel Transcriptional Targets of the SRY-HMG Box Transcription Factor SOX4 Link Its Expression to the Development of Small Cell Lung Cancer

Sandra Castillo Ander Matheu Niccolò Mariani Julián Carretero Fernando López‐Ríos

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Testis determining factor

SOX4

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