Lukas C. Amler

PCR Oncology

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i-10 index

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Document Type

Co-Authors

Mark R. Lackner

Ideaya Biosciences (United States)

129

Carol O’Brien

University of Canberra

Garret M. Hampton

La Roche College

Guy Cavet

Flatiron Health (United States)

Heidi Savage

King's College London

David S. Shames

Marker Gene Technologies (United States)

Sankar Mohan

Simon Fraser University

Yibing Yan

First Affiliated Hospital of Henan University

Elizabeth A. Punnoose

Deutschen Konsortium für Translationale Krebsforschung

Xiaolan Hu

Macau University of Science and Technology

Cooperative Institutions

Genentech

133

Dana-Farber Cancer Institute

Memorial Sloan Kettering Cancer Center

University of California, San Francisco

Sarah Cannon

La Roche College

Harvard University

The University of Texas MD Anderson Cancer Center

Roche (United States)

Molecular Oncology (United States)

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Data from Dual Targeting of EGFR and HER3 with MEHD7945A Overcomes Acquired Resistance to EGFR Inhibitors and Radiation

Shyhmin Huang Chunrong Li Eric A. Armstrong Chimera R. Peet Jarob Saker

<div>AbstractEGF receptor (EGFR) inhibition is efficacious in cancer therapy, but initially sensitive tumors often develop resistance. In this study, we investigated the potential to overcome acquired resistance to EGFR inhibitors with MEHD7945A, a monoclonal antibody that dually targets EGFR and HER3 (ErbB3). In cancer cells resistant to cetuximab and erlotinib, we found that MEHD7945A, but not single target EGFR inhibitors, could inhibit tumor growth and cell-cycle progression in parallel with EGFR/HER3 signaling pathway modulation. MEHD7945A was more effective than a combination of cetuximab and anti-HER3 antibody at inhibiting both EGFR/HER3 signaling and tumor growth. In human tumor xenograft models, we confirmed the greater antitumor potency of MEHD7945A than cetuximab or erlotinib. MEHD7945A retained potent activity in tumors refractory to EGFR inhibitor alone. Furthermore, MEHD7945A also limited cross-resistance to radiation in EGFR inhibitor–resistant cells by modulating cell-cycle progression and repair processes that control apoptotic cell death. Taken together, our findings confirm an important role of compensatory HER3 signaling in the development of acquired resistance to EGFR inhibitors and offer preclinical proof-of-concept that MEHD7945A can effectively overcome EGFR inhibitor resistance. Cancer Res; 73(2); 824–33. ©2012 AACR.</div>

Acquired resistance

EGFR Inhibitors

10.1158/0008-5472.c.6505176.v1

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Supplementary Tables 5 - 10 from High-Throughput Detection of Clinically Relevant Mutations in Archived Tumor Samples by Multiplexed PCR and Next-Generation Sequencing

Richard Bourgon Shan Lu Yibing Yan Mark R. Lackner Weiru Wang

XLSX file - 602KB, Supplementary Table 5. Cancer cell lines analyzed in this study. Supplementary Table 6. Tumor tissues analyzed in this study. Supplementary Table 7. List of 340 well characterized hotspot mutations interrogated by the amplicon libraries in this study. Variants also assayed by asPCR are indicated. Supplementary Table 8. Variants detected in 66 cancer cell lines, after applying post-processing filters. Note that indels and predicted deleterious SNVs are reported for all interrogated genes and transcripts. Supplementary Table 9. Variants detected in 73 FFPE endometrial tumor tissues, after applying post-processing filters. Note that indels and predicted deleterious SNVs are reported for all interrogated genes and transcripts. Supplementary Table 10. For cell line data, concordance with COSMIC somatic mutation annotation.

Indel

Concordance

Amplicon

Table (database)

10.1158/1078-0432.22454519.v1

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Data from Upregulation of Periostin and Reactive Stroma Is Associated with Primary Chemoresistance and Predicts Clinical Outcomes in Epithelial Ovarian Cancer

Lisa Ryner Y. Guan Ron Firestein Yuanyuan Xiao Younjeong Choi

<div>AbstractPurpose: Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatment. However, predictive and therapeutic strategies are lacking due to a poor understanding of the underlying molecular mechanisms. This study aimed to identify key molecular characteristics that are associated with primary chemoresistance in epithelial ovarian cancers.Experimental Design: Gene expression profiling was performed on a discovery set of 85 ovarian tumors with clinically well-defined response to chemotherapies as well as on an independent validation dataset containing 138 ovarian patients from the chemotreatment arm of the ICON7 trial.Results: We identified a distinct “reactive stroma” gene signature that is specifically associated with primary chemoresistant tumors and was further upregulated in posttreatment recurrent tumors. Immunohistochemistry (IHC) and RNA in situ hybridization (RNA ISH) analyses on three of the highest-ranked signature genes (POSTN, LOX, and FAP) confirmed that modulation of the reactive stroma signature genes within the peritumoral stromal compartments was specifically associated with the clinical chemoresistance. Consistent with these findings, chemosensitive ovarian cells grown in the presence of recombinant POSTN promoted resistance to carboplatin and paclitaxel treatment in vitro. Finally, we validated the reactive stroma signature in an independent dataset and demonstrated that a high POSTN expression level predicts shorter progression-free survival following first-line chemotherapy.Conclusions: Our findings highlight the important interplay between cancer and the tumor microenvironment in ovarian cancer biology and treatment. The identified reactive stromal components in this study provide a molecular basis to the further development of novel diagnostic and therapeutic strategies for overcoming chemoresistance in ovarian cancer. Clin Cancer Res; 21(13); 2941–51. ©2015 AACR.</div>

Periostin

Carboplatin

Gene signature

10.1158/1078-0432.c.6523293

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A whole-genome RNAi screen identifies an 8q22 gene cluster that inhibits death receptor-mediated apoptosis

Proceedings of the National Academy of Sciences (2011)

Nicholas Dompe Celina Sanchez Rivers Li Li Shaun Cordes Martin Schwickart

Deregulation of apoptosis is a common occurrence in cancer, for which emerging oncology therapeutic agents designed to engage this pathway are undergoing clinical trials. With the aim of uncovering strategies to activate apoptosis in cancer cells, we used a pooled shRNA screen to interrogate death receptor signaling. This screening approach identified 16 genes that modulate the sensitivity to ligand induced apoptosis, with several genes exhibiting frequent overexpression and/or copy number gain in cancer. Interestingly, two of the top hits, EDD1 and GRHL2, are found 50 kb apart on chromosome 8q22, a region that is frequently amplified in many cancers. By using a series of silencing and overexpression studies, we show that EDD1 and GRHL2 suppress death-receptor expression, and that EDD1 expression is elevated in breast, pancreas, and lung cancer cell lines resistant to death receptor-mediated apoptosis. Supporting the relevance of EDD1 and GRHL2 as therapeutic candidates to engage apoptosis in cancer cells, silencing the expression of either gene sensitizes 8q22-amplified breast cancer cell lines to death receptor induced apoptosis. Our findings highlight a mechanism by which cancer cells may evade apoptosis, and therefore provide insight in the search for new targets and functional biomarkers for this pathway.

10.1073/pnas.1100132108

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Citations (58)

Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL

Nature Medicine (2007)

Klaus W. Wagner Elizabeth A. Punnoose Thomas Januario David A. Lawrence Robert Pitti

Ectodomain

N-linked glycosylation

10.1038/nm1627

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Citations (590)

Supplementary Methods from Phosphoinositide 3-Kinase (PI3K) Pathway Alterations Are Associated with Histologic Subtypes and Are Predictive of Sensitivity to PI3K Inhibitors in Lung Cancer Preclinical Models

Jill M. Spoerke Carol O’Brien Ling Huw Hartmut Koeppen Jane Fridlyand

PDF file - 110K

Phosphoinositide 3-kinase

10.1158/1078-0432.22451103

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Supplementary Figure 1 from Dual Targeting of EGFR and HER3 with MEHD7945A Overcomes Acquired Resistance to EGFR Inhibitors and Radiation

Shyhmin Huang Chunrong Li Eric A. Armstrong Chimera R. Peet Jarob Saker

PDF file - 23KB, Effect of MEHD7945A on cell cycle progression and EGFR/HER3 signaling

EGFR Inhibitors

10.1158/0008-5472.22398888.v1

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CCR Translation for this Article from Predictive Biomarkers of Sensitivity to the Phosphatidylinositol 3′ Kinase Inhibitor GDC-0941 in Breast Cancer Preclinical Models

Carol O’Brien Jeffrey J. Wallin Deepak Sampath Debraj GuhaThakurta Heidi Savage

CCR Translation for this Article from Predictive Biomarkers of Sensitivity to the Phosphatidylinositol 3′ Kinase Inhibitor GDC-0941 in Breast Cancer Preclinical Models

10.1158/1078-0432.22442274.v1

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Supplementary Figure Legends from Dual Targeting of EGFR and HER3 with MEHD7945A Overcomes Acquired Resistance to EGFR Inhibitors and Radiation

Shyhmin Huang Chunrong Li Eric A. Armstrong Chimera R. Peet Jarob Saker

PDF file - 63KB, Supplementary Figure Legends

Acquired resistance

10.1158/0008-5472.22398879

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Jill M. Spoerke Carol O’Brien Ling Huw Hartmut Koeppen Jane Fridlyand

PDF file - 110K

Phosphoinositide 3-kinase

10.1158/1078-0432.22451103.v1

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