Christopher M. Counter
· George Barth Geller Distinguished Professor of PharmacologyVerifiedDuke University · Cellular and Molecular Biology
Active 1992–2026
About
Christopher M. Counter is the George Barth Geller Distinguished Professor of Pharmacology and a Professor of Pharmacology and Cancer Biology at Duke University School of Medicine. He also holds positions as an Assistant Professor in Radiation Oncology and as a Professor of Cell Biology. He is a member of the Duke Cancer Institute. His primary research focuses on pharmacology, cancer biology, and cell biology, contributing to the understanding of molecular mechanisms underlying cancer and therapeutic interventions. His academic and research roles are centered at Duke University, where he is involved in teaching and advancing research in these fields.
Research topics
- Genetics
- Biology
- Cancer research
- Cell biology
- Molecular biology
Selected publications
Editorial Expression of Concern: Creation of human tumour cells with defined genetic elements
Nature · 2026-04-15
articleCancer Research · 2026-01-13 · 2 citations
articleOpen accessPatients with pancreatic ductal adenocarcinoma (PDAC) harboring KRASG12R mutations have increased overall survival relative to patients with KRASG12D/V mutations. To investigate the mechanisms underlying this differential outcome, we developed a genetically engineered mouse model (GEMM) harboring KrasG12R and Trp53R172H mutations (KrasLSL-G12R/+;Trp53LSL-R172H/+;p48Cre-ERTM). Unlike KrasG12D models, KrasG12R GEMMs exhibited limited tumorigenesis, with only 10% developing pancreatic tumors after 1 year. Additionally, mice harboring whole-body expression of KrasG12R remained healthy for over 1 year, whereas KrasG12D mice developed rapid multifocal disease. Comparison of KRAS mutant-selective transcription and signaling in murine and human PDAC cell lines, GEMMs, and patient-derived xenograft (PDX) mouse models revealed that direct KRAS-mediated PI3K activation is necessary for robust tumor initiation in GEMMs. Unexpectedly, KRAS was not the primary driver of PI3K activity in human PDAC cell lines and PDX models, regardless of KRAS mutation. KRASG12R and KRASG12D activated a similar pancreas-specific transcriptional network, but KRASG12R promoted these pathways less robustly due to limited ERK/MAPK nuclear translocation. Finally, KRASG12R human pancreatic tumors had an altered tumor microenvironment (TME) with reduced collagen deposition and metastatic liver invasion. Together, this study demonstrated that KRASG12R is capable of driving tumorigenesis despite the reduced ERK/MAPK nuclear translocation and transcriptional output. Although human KRASG12D- and KRASG12R-mutant tumors display unexpected similarities in PI3K activity, the differential ERK/MAPK signaling activity and the extrinsic consequences on the TME provide support for using KRASG12R mutation status as a prognostic biomarker for therapeutic strategies. SIGNIFICANCE: KRASG12R-mutant pancreatic cancer is characterized by lower ERK/MAPK nuclear translocation and transcriptional output than KRASG12D-mutant tumors, offering a potential window for patients with KRASG12R mutations to derive additional benefit from neoadjuvant therapy. See related commentary by Tiriac and Engle, p. 1817 See related article by Burge et al., p. 1854 See related article by Kamgar et al., p. 2042.
Profiling KRAS mutations in whole blood by error-corrected maximum depth sequencing
npj Precision Oncology · 2026-04-03
articleOpen accessSenior authorClinical use of circulating tumor DNA (ctDNA) sequencing is rapidly increasing, but performance is limited by the sensitivity of next generation sequencing and relies on specialized sample collection. Here we describe sequencing the most frequently mutated oncogene KRAS by adapting error-corrected Maximum Depth Sequencing (K-MDS) for whole blood. K-MDS detected oncogenic KRAS mutations of cancer cells spiked into healthy human blood at a dilution as low as 0.001% with 100% specificity. In a prospectively collected cohort of 190 advanced cancer patients with solid tumors having concurrent commercial ctDNA testing or tumor sequencing, K-MDS detected commercially-identified oncogenic KRAS mutations in 88% of cases. Assay specificity was increased by analyzing both the forward and reverse strands and assigning mutation-specific detection thresholds. Sequencing both strands by K-MDS revealed that the assay differed from the commercial test in two small subsets of the primary cohort. First, multiple oncogenic KRAS mutations were uniquely detected by K-MDS in 7 of 9 patients having prior treatment with EGFR or KRAS inhibitors. Second, in 12 patients with bone metastases, K-MDS detected KRAS mutations more often (10 versus 5) than the commercial ctDNA assay. The sensitivity of the assay suggests potential utility in settings of potentially low ctDNA burden. To this end, when applied to preoperative blood samples collected from a pilot cohort of 18 pancreas adenocarcinoma patients undergoing curative intent resection, K-MDS stratified these patients based on their risk of metastatic disease recurrence. This first-in-human experience with K-MDS suggests the assay has the potential to complement current commercial ctDNA assays for targeted detection of oncogenic mutations in patient whole blood.
Loss of inducible nitric oxide synthase promotes Kras/Pten-driven lung tumorigenesis
Frontiers in Cell and Developmental Biology · 2026-02-27
articleOpen accessSenior authorynthase (iNOS) enzyme has been implicated in both pro- and anti-tumorigenic processes, depending on the cancer context. In oncogenic Kras-driven mouse models of lung adenocarcinoma, the loss of iNOS reduces tumorigenesis. To explore the additional loss of the tumor suppressor Pten in this setting, we compared lung tumorigenesis in mice induced by activation of oncogenic Kras in conjunction with inactivation of Pten in the absence and presence of iNOS. We report that the loss of iNOS did not affect the number or type of lung lesions compared to control iNOS wild-type mice, but was associated with shortened overall survival that was accompanired by increased tumor burden and intratumoral macrophage infiltration. These findings suggest that the antineoplastic effect of iNOS deficiency in Kras-driven lung tumorigenesis is reversed upon the loss of Pten. Thus, even within the identical cancer model, the loss of iNOS can have opposite effects depending on the genetic context.
Journal of Clinical Oncology · 2025-05-28
articleSenior author4156 Background: Pancreatic Ductal Adenocarcinoma (PDAC) is a leading cause of cancer death and mortality is increasing. A contributor to poor outcomes is the absence of non-invasivebiomarkers for disease screening, treatment monitoring, and identification of therapeutic targets. Blood-based profiling of circulating tumor DNA (ctDNA) using Next Generation Sequencing (NGS) has addressed these needs in several cancer types, but available commercial ctDNA assays are not as effective in PDAC. To address this unmet clinical need, we developed an ultra-sensitive sequencing assay to detect mutant KRAS in the whole blood of PDAC patients. Methods: We adapted the bacterial Maximum Depth Sequencing (MDS) assay for Human whole blood MDS (hMDS) to improve upon the sensitivity of NGS by barcoding DNA fragments with unique molecular identifiers prior to performing multiple rounds of first-strand synthesis to resolve sequencing errors. Analytic sensitivity was evaluated by spiking PDAC cells at various dilutions into control blood isolated from 10 individuals and assaying the mixture by hMDS in triplicate. Clinical sensitivity was then evaluated by collecting paired blood draws from 200 advanced PDAC patients in prospective fashion, one to be tested with a commercial ctDNA test and one by hMDS. Results: ThehMDS assay reproducibly detected PDAC cells at dilutions as low as one cell per mL or one mutated fragment per million KRAS fragments. Thus, hMDS reached an analytic sensitivity 1000x higher than NGS. Clonal KRAS mutations were detected in 179 of the first 194 patient samples (92.2%), surpassing historical commercial detection rates of 50% by commercial ctDNA assays. Mutations were reproducibly detected in replicate analysis of forward and reverse DNA strands. Weak clonal KRAS activating mutations were also detected in several non-cancer, control patients. Conclusions: We developed an assay capable of sensitively detecting PDAC ctDNA in whole blood. Formal comparison to commercial testing is ongoing, but preliminary results suggest this assay could be a sensitive tool for non-invasive PDAC mutation profiling and disease monitoring. The presence of weak clonal KRAS mutations in control patients has motivated development of a multiplex platform capable of screening for mutations in multiple driver genes.
CDK8 Inhibition Releases the Muscle Differentiation Block in Fusion-driven Alveolar Rhabdomyosarcoma
bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-18
preprintOpen accessABSTRACT Alveolar rhabdomyosarcoma (aRMS) is a fusion-driven pediatric cancer with poor survival and limited therapeutic options. To uncover novel vulnerabilities, we employed complex-based analysis of the DepMap functional genomic data, identifying CDK8 as a dependency in aRMS. Both CDK8 knockout and pharmacologic inhibition impaired tumor cell growth and induced myogenic differentiation in vitro and in vivo . Compared to genetic loss, CDK8 inhibition induced more dynamic transcriptional changes. With a genome-scale CRISPR-Cas9 drug modifier screen, we determined that the maximal anti-tumor activity of the CDK8 inhibitor requires the presence of the Mediator kinase module and transcriptional cooperation with the SAGA complex. We further identified SIX4 as a key transcription factor mediating CDK8 inhibitor-induced transcriptional activation of myogenic differentiation genes and tumor cell proliferation. These findings suggest a distinct gain-of-function mechanism of the CDK8 inhibitor and establish a strong rationale for CDK8 inhibition as a differentiation-inducing therapeutic strategy in aRMS. STATEMENT OF SIGNIFICANCE We provide a framework for uncovering therapeutic targets by network-based analysis of functional genomic screens. We identify CDK8 as a druggable target in aRMS and determine that CDK8 inhibition drives myogenic differentiation and impairs tumor progression via a collaborative mechanism involving the Mediator kinase module, SAGA complex, and SIX4.
Cancer Research · 2025-09-25
articleAbstract Functional and chemical genomic approaches, such as the Broad Institute’s Cancer Dependency Map and PRISM (Profiling Relative Inhibition Simultaneously in Mixtures) chemical screening, have revolutionized the identification of context-specific genetic dependencies and therapeutic vulnerabilities across diverse cancer types. These datasets empower the identification of therapeutic strategies in cancers with limited actionable mutations. Alveolar rhabdomyosarcoma (aRMS), a pediatric cancer driven by a hard-to-target fusion oncoprotein, PAX3::FOXO1, typically expresses no immediately actionable mutations. Using aRMS as a disease model, we utilized the Broad Institute’s Cancer Dependency Map dataset, coupled with single-sample gene set enrichment analysis (ssGSEA), to systematically assess protein complex dependencies in aRMS. We nominated the Mediator complex and further identified CDK8, a member of the Mediator kinase module, as a clinically actionable target in aRMS. Other members of the Mediator kinase module, including CCNC, MED12, and MED13, are also essential to aRMS proliferation. In addition, in aRMS cell lines, there was a positive correlation (R=0.68) between the CDK8 gene-effect score and the effect of the CDK8 inhibitor, BI-1347, in the PRISM screening. We validated that both genetic loss of CDK8 and kinase inhibition by CDK8 small molecule inhibitors impaired aRMS cell line growth in vitro and induced evidence of myogenic differentiation. Our in vivo studies demonstrated that the clinical grade CDK8 inhibitor SEL-120-34A decreased aRMS cell line xenograft tumor growth. Functional genomic screens also serve as powerful tools to understand the mechanisms of small molecule inhibitors and to identify resistance and sensitizer mechanisms. We thus performed an unbiased genome-scale CRISPR-Cas9 screen with the CDK8 inhibitor BI-1347 in aRMS. We determined that the maximal anti-tumor activity of the CDK8 inhibitor requires the presence of the SAGA complex, particularly the SAGA HAT module. We further identified SIX4 as a key transcription factor mediating CDK8 inhibitor-induced transcriptional activation of myogenic differentiation genes. In addition, we revealed that the maximal activity of BI-1347 requires the presence of the Mediator kinase module, suggesting a trapping-related mechanism in addition to kinase enzymatic inhibition. Accordingly, we found that CDK8 inhibition increased the binding of components of the Mediator kinase module and SIX4 and TADA2B at enhancers of terminal muscle differentiation-related genes, such as VGLL2, SEMA3D, MYL1, leading to their transcriptional activation, as shown by PRO-seq analyses. These findings provide a framework for uncovering therapeutic targets using network-based analysis of functional genomic screens, and for studying the small molecular inhibitor mechanisms. In aRMS, CDK8 inhibition is a differentiation-inducing therapeutic strategy. Citation Format: Susu Zhang, Kathleen Engel, Assil Fahs, Clare Malone, Kenneth Ross, Marissa Just, Brian Guedes, Diyana Granum, Kristianne M Oristian, Alexander Kovach, Gabriela Alexe, Giulia Digiovanni, Leen Barbar, Rex Bentley, Christian Cerda-Smith, Ozgun Le Roux, Elizabeth Mendes, Seth P Zimmerman, Matthew Rees, Jennifer Roth, Jack F Shern, Kris C Wood, Christopher M Counter, Corinne M Linardic, Kimberly Stegmaier. CDK8 Inhibition Releases the Muscle Differentiation Block in Fusion-Driven Alveolar Rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr A022-PR005.
The essential clathrin adapter protein complex-2 is tumor suppressive specifically in vivo
Nature Communications · 2025-03-06 · 1 citations
articleOpen accessSenior authorCorrespondingThe microenvironment is a rich source of new cancer targets. We thus used a targeted single-guide RNA library to screen a panel of human pancreatic cancer lines for genes uniquely affecting tumorigenesis. Here we show inactivation of the Adapter Protein complex-2 of clathrin-mediated endocytosis reduces cell growth in vitro, but completely oppositely, promotes tumor growth in vivo. In culture, loss of the complex reduces transferrin endocytosis and iron import required for cell fitness. In tumors, alternative iron transport pathways allow pro-tumor effects of Adapter Protein complex-2 loss to manifest. In the most sensitive case, this is attributed to reprogramming the plasma membrane proteome, retaining integrins on the surface leading to Focal Adhesion Kinase phosphorylation and induction of proliferative signals. Adapter Protein complex-2 function in tumorigenesis is thus dependent upon the microenvironment, behaving as a common essential gene in culture via iron import, but as a tumor suppressor in tumors via integrin trafficking.
UNC Libraries · 2024-08-29
articleOpen accessCancer Research · 2024-09-15
articleSenior authorAbstract Introduction: One barrier to improving Pancreatic Ductal Adenocarcinoma (PDAC) patient outcomes is the absence of effective, non-invasive biomarkers for disease screening, treatment monitoring, and identification of therapeutic targets. While sequencing-based approaches to detect mutant circulating tumor DNA (ctDNA) in blood have transformed clinical management in several cancer types, use of these ‘liquid biopsies’ has lagged behind in PDAC due to low shedding of PDAC tumor cells. Nevertheless, intact circulating tumor cells have been documented in even the earliest stages of PDAC and precede the limits of disease detection on imaging or gross histology in mouse models. This suggests that circulating tumor cells could server as a PDAC biomarker if the sensitivity of sequencing could be increased. Methods: Point mutations in the gene KRAS are found in up to 95% of PDAC patients and hence represent a potential biomarker target for this cancer. To detect these pathogenic mutations in KRAS, we will adapt Maximum Depth Sequencing (MDS) for exon 2 of this gene by testing various primers and reaction conditions. The sensitivity of the K-MDS assay was optimized for blood by spiking PDAC cells with known KRAS mutations into healthy control blood at various dilutions. Finally, to evaluate the clinical sensitivity, we have collected paired blood draws from 200 advanced PDAC patients in prospective fashion, one to be tested with a commercial ctDNA test and one by K-MDS. Results: We optimized MDS to sequence exon 2 of KRAS and successfully detected a single mutant template in >107recovered independently barcoded templates (e.g. 107 individual KRAS alleles). We then optimized the assay for human blood and demonstrated that K-MDS could reproducibly detect a KRAS mutation corresponding to PDAC cells spiked into healthy control whole blood at the lowest dilution tested, namely one cell per ml of blood. This corresponds to a sensitivity of one mutated fragment per one million KRAS fragments, or 1000x more sensitive than currently available commercial assays. We are currently performing K-MDS on prospective PDAC cohort, with completion of this study expected this fall. Conclusions: We developed a highly sensitive sequencing assay cable of detecting PDAC ctDNA in whole blood. With successful validation in PDAC blood samples, this assay could provide a powerful tool for non-invasive PDAC mutation profiling and disease monitoring. Citation Format: Ryne Ramaker, James Abbruzzese, Chris Counter. Development of an ultrasensitive sequencing platform for blood-based mutation profiling of pancreas cancer patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B021.
Recent grants
NIH · $343k · 2009
NIH · $3.5M · 2019
NIH · $152k · 2014
NIH · $4.1M · 2019
NIH · $2.9M · 2009
Frequent coauthors
- 38 shared
Robert A. Weinberg
Whitehead Institute for Biomedical Research
- 34 shared
Kian‐Huat Lim
- 31 shared
Silvia Bacchetti
- 30 shared
David F. Kashatus
University of Virginia
- 28 shared
Calvin B. Harley
- 27 shared
Carol W. Greider
University of California, Santa Cruz
- 27 shared
Donita C. Brady
- 26 shared
William C. Hahn
Dana-Farber Cancer Institute
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