Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors

Schütte, Moritz; Risch, Thomas S.; Abdavi-Azar, Nilofar; Boehnke, Karsten; Schumacher, Dirk; Keil, Marlen; Yildiriman, Reha; Jandrasits, Christine; Borodina, Tatiana; Amtislavskiy, Vyacheslav; Worth, Catherine L.; Schweiger, Caroline; Liebs, Sandra; Lange, Martin; Warnatz, Hans Jörg; Butcher, Lee M.; Barrett, James E.; Sultan, Marc; Wierling, Christoph; Golob-Schwarzl, Nicole; Lax, Sigurd; Uranitsch, Stefan; Becker, Michael W.; Welte, Yvonne; Regan, Joseph L.; Silvestrov, Maxine; Kehler, Inge; Fusi, Alberto; Keßler, T.; Herwig, Ralf; Landegren, Ulf; Wienke, Dirk; Nilsson, Mats; Velasco, Juan A.; Garin‐Chesa, Pilar; Reinhard, Christoph; Beck, Stephan; Schäfer, Reinhold; Regenbrecht, Christian; Henderson, David; Lange, Bodo; Haybaeck, Johannes; Keilholz, Ulrich; Hoffmann, Jens; Lehrach, Hans; Yaspo, Marie–Laure

doi:10.1038/ncomms14262

Cited by 280 publications

(372 citation statements)

References 75 publications

(114 reference statements)

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“…Importantly, the classifier performed well also in tumor samples, confirming reproducibility of the classification in primary colorectal cancers, and showing translation of the classification to PDX models, where contamination of gene expression signals from murine stroma may be a challenge. It has recently been recognized also by others that the original CMS classifier fails to identify some of the CMS groups not only in cell lines, but also in patientderived organoids and xenografts (50). We argue that this may be alleviated by our adapted classifier.…”

Section: Discussionmentioning

confidence: 85%

“…S11A). Similarly, among 32 colorectal cancer cell lines from the Genomics of Drug Sensitivity in Cancer Project (16 overlapping with our drug screen), higher sensitivity to the HSP90 inhibitor CCT018159 was confirmed in CMS1/4 [average log e (IC 50 in mmol/L) 3.4] compared with CMS2/3 [average log e (IC 50 in mmol/L) 5.6, P ¼ 0.0004 by Welch t test]. Here, stronger relative sensitivity in CMS1/4 was found also among MSS cell lines only (Supplementary Fig.…”

Section: Strong Relative Activity Of Hsp90 Inhibitors In Cms1 and Cmsmentioning

confidence: 99%

“…The cell lines were classified using the adapted classifier and the CMS1/4 group was found to have lower IC 50 -values for ganetespib (mean 24 nmol/L) than CMS2/3 (mean 52 nmol/L), indicating higher sensitivity in the first group (Supplementary Fig. S11A).…”

Section: Strong Relative Activity Of Hsp90 Inhibitors In Cms1 and Cmsmentioning

confidence: 99%

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Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies

Sveen

Bruun

Eide

et al. 2018

Clinical Cancer Research

204

213

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Purpose: Response to standard oncologic treatment is limited in colorectal cancer. The gene expression-based consensus molecular subtypes (CMS) provide a new paradigm for stratified treatment and drug repurposing; however, drug discovery is currently limited by the lack of translation of CMS to preclinical models.Experimental Design: We analyzed CMS in primary colorectal cancers, cell lines, and patient-derived xenografts (PDX). For classification of preclinical models, we developed an optimized classifier enriched for cancer cell-intrinsic gene expression signals, and performed high-throughput in vitro drug screening (n ¼ 459 drugs) to analyze subtype-specific drug sensitivities.Results: The distinct molecular and clinicopathologic characteristics of each CMS group were validated in a single-hospital series of 409 primary colorectal cancers. The new, cancer cell-adapted classifier was found to perform well in primary tumors, and applied to a panel of 148 cell lines and 32 PDXs, these colorectal cancer models were shown to recapitulate the biology of the CMS groups. Drug screening of 33 cell lines demonstrated subtype-dependent response profiles, confirming strong response to EGFR and HER2 inhibitors in the CMS2 epithelial/canonical group, and revealing strong sensitivity to HSP90 inhibitors in cells with the CMS1 microsatellite instability/immune and CMS4 mesenchymal phenotypes. This association was validated in vitro in additional CMS-predicted cell lines. Combination treatment with 5-fluorouracil and luminespib showed potential to alleviate chemoresistance in a CMS4 PDX model, an effect not seen in a chemosensitive CMS2 PDX model.Conclusions: We provide translation of CMS classification to preclinical models and uncover a potential for targeted treatment repurposing in the chemoresistant CMS4 group.

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Section: Discussionmentioning

confidence: 85%

Section: Strong Relative Activity Of Hsp90 Inhibitors In Cms1 and Cmsmentioning

confidence: 99%

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Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies

Sveen

Bruun

Eide

et al. 2018

Clinical Cancer Research

204

213

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“…Many forms of cancer are associated with gene fusions promoting tumorigenesis. Gene fusions typically result from chromosomal translocations, deletions, or inversions but, for technical reasons, those cancer-relevant events are usually much easier to identify in RNAseq experiments (e.g., [20] ).…”

Section: Is More More?mentioning

confidence: 99%

Cancer Precision Medicine: Why More Is More and DNA Is Not Enough

Schütte

Ogilvie

Rieke

et al. 2017

Public Health Genomics

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Every tumour is different. They arise in patients with different genomes, from cells with different epigenetic modifications, and by random processes affecting the genome and/or epigenome of a somatic cell, allowing it to escape the usual controls on its growth. Tumours and patients therefore often respond very differently to the drugs they receive. Cancer precision medicine aims to characterise the tumour (and often also the patient) to be able to predict, with high accuracy, its response to different treatments, with options ranging from the selective characterisation of a few genomic variants considered particularly important to predict the response of the tumour to specific drugs, to deep genome analysis of both tumour and patient, combined with deep transcriptome analysis of the tumour. Here, we compare the expected results of carrying out such analyses at different levels, from different size panels to a comprehensive analysis incorporating both patient and tumour at the DNA and RNA levels. In doing so, we illustrate the additional power gained by this unusually deep analysis strategy, a potential basis for a future precision medicine first strategy in cancer drug therapy. However, this is only a step along the way of increasingly detailed molecular characterisation, which in our view will, in the future, introduce additional molecular characterisation techniques, including systematic analysis of proteins and protein modification states and different types of metabolites in the tumour, systematic analysis of circulating tumour cells and nucleic acids, the use of spatially resolved analysis techniques to address the problem of tumour heterogeneity as well as the deep analyses of the immune system of the patient to, e.g., predict the response of the patient to different types of immunotherapy. Such analyses will generate data sets of even greater complexity, requiring mechanistic modelling approaches to capture enough of the complex situation in the real patient to be able to accurately predict his/her responses to all available therapies.

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“…We and others have shown, that the molecular make-up of the primary tumor genomic as well as transcriptomic alterations are preserved throughout organoid propagation (Dr. Chantal Pauli, personal communication) (12). The ability to capture tumor heterogeneity makes organoids superior to traditional cancer cell lines (13,14).…”

Section: Discussionmentioning

confidence: 99%

On-site Cytology for Development of Patient-Derived Three-dimensional Organoid Cultures – A Pilot Study

Sailer

Pauli

Merzier

et al. 2017

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Abstract. Background/Aim: Development of patient-derived three-dimensional (3D) organoid cultures is an emerging technique in the field of precision oncology. We aimed to integrate on-site adequacy evaluation using cytology into the tumor organoid development workflow to ensure precise characterization and growth of these cultures. Patients andPersonalized medicine, also referred to as Precision Medicine (PM), is the approach to treat a patient's disease by taking into account the molecular landscape of the individual tumor or disease process. In addition to its role in oncology, PM is also employed in the treatment of other chronic conditions such as autoimmune disorders. In the United States, the Precision Medicine Initiative ® was launched by President Barack Obama in early 2015 in order to facilitate individualized patient care. Recently, the National Institute of Health (NIH) awarded $55 million to enroll one million patients in a multi-institutional precision medicine trial (1).In the field of Precision Oncology, the development of patient-derived 3D tumor organoid cultures is an emerging model that can be a valuable tool for predictive in vitro drug testing (2). Although cell lines have long been established for preclinical drug testing, they do not sufficiently recapitulate the innate tumor heterogeneity and therefore the genomic complexity. Organoid cultures are thus the preferable method for predictive drug testing (3). Organoids are derived from stem cells and are self-organizing and selfrenewing (4). Since organoids maintain the genetic representation of a patient's tumor, they are a readily available source of high-quality DNA and RNA for next generation sequencing (NGS). In order to initiate organoid development, fresh tumor tissue is collected and processed 1569This article is freely accessible online. Organoid development is a time-and cost-intense process. As yet, no cost estimate per organoid development has been published. Organoids are usually propagated in Matrigel Matrix (Corning Inc. USA), which closely resembles extracellular matrix. It provides a scaffold for cells to grow and proliferate (7). Matrigel is a relatively expensive medium priced at approximately $318 per bottle. Costs for technical staff adds to the expenditure for cell culture infrastructure and consumables. Submitting tissue for organoid development "blindly", i.e. without prior characterization, can result in spending money and time propagating benign organoids. Submitting only lesional tissue for further processing is therefore paramount. Rapid on-site evaluation (ROSE) is a common practice in cytopathology that assesses tissue samples for adequacy of material for diagnostic purposes. We have recently shown, that cytological evaluation of organoids within a few weeks into their development can successfully characterize them (8). In the present study, we aimed to integrate on-site cytological evaluation during tissue collection to identify viable tumor for organoid development and guide decision-making on the early fate ...

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Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors

Cited by 280 publications

References 75 publications

Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies

Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies

Cancer Precision Medicine: Why More Is More and DNA Is Not Enough

On-site Cytology for Development of Patient-Derived Three-dimensional Organoid Cultures – A Pilot Study

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