Cory M. Johannessen
A5022484206- Melanoma and MAPK Pathways
- Protein Degradation and Inhibitors
- Computational Drug Discovery Methods
- Cancer Mechanisms and Therapy
- BRCA gene mutations in cancer
- Synthesis and biological activity
- CRISPR and Genetic Engineering
- Cancer Genomics and Diagnostics
- Chromatin Remodeling and Cancer
- Lung Cancer Treatments and Mutations
- Genetics, Bioinformatics, and Biomedical Research
- Cancer therapeutics and mechanisms
- Circular RNAs in diseases
- MicroRNA in disease regulation
- CAR-T cell therapy research
- Cell Image Analysis Techniques
- Ovarian cancer diagnosis and treatment
- Bioinformatics and Genomic Networks
- Cancer Research and Treatments
- Single-cell and spatial transcriptomics
- Synthesis of Tetrazole Derivatives
- DNA Repair Mechanisms
- RNA Interference and Gene Delivery
- Cutaneous Melanoma Detection and Management
- Advanced Breast Cancer Therapies
Broad Institute
2016-2025
Massachusetts Institute of Technology
2010-2025
Dana-Farber Cancer Institute
2011-2025
Harvard University
2002-2025
Novartis (United States)
2022
Novartis (Germany)
2021
Target (United States)
2021
Novartis Institutes for BioMedical Research
2021
Massachusetts General Hospital
2002-2013
Brigham and Women's Hospital
2005-2013
To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, endothelial cells. Malignant within same tumor displayed transcriptional heterogeneity associated with cell cycle, spatial context, a drug-resistance program. In particular, all tumors harbored malignant two states, such that characterized by high levels MITF transcription factor also...
A detailed understanding of the mechanisms by which tumors acquire resistance to targeted anticancer agents should speed development treatment strategies with lasting clinical efficacy. RAF inhibition in BRAF-mutant melanoma exemplifies promise and challenge many drugs; although response rates are high, invariably develops. Here, we articulate overarching principles kinase inhibitors, as well a translational approach characterize setting through tumor mutation profiling. As proof principle,...
Most patients with BRAF(V600)-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic mechanisms inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known putative inhibitor genes were observed 23 (51%). Besides previously characterized alterations, we...
Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies content in 0.1× coverage whole-genome data without prior knowledge mutations. We apply ichorCNA to 1439 samples 520 patients with metastatic prostate or breast cancers. In earliest tested sample for each patient, 34% have ≥10% tumor-derived cfDNA, sufficient...
Loss-of-function mutations in the NF1 tumor suppressor gene underlie familial cancer syndrome neurofibromatosis type I (NF1). The -encoded protein, neurofibromin, functions as a Ras-GTPase activating protein (RasGAP). Accordingly, deregulation of Ras is thought to contribute development. However, critical effector pathways involved disease pathogenesis are still unknown. We show here that mTOR pathway tightly regulated by neurofibromin. constitutively activated both -deficient primary cells...
Most melanomas harbor oncogenic BRAF(V600) mutations, which constitutively activate the MAPK pathway. Although pathway inhibitors show clinical benefit in BRAF(V600)-mutant melanoma, it remains incompletely understood why 10% to 20% of patients fail respond. Here, we that RAF inhibitor-sensitive and inhibitor-resistant display distinct transcriptional profiles. Whereas most drug-sensitive cell lines patient biopsies showed high expression activity melanocytic lineage transcription factor...
Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF the downstream MAP-ERK kinase (MEK)1 MEK2 kinases, respectively, improves progression-free survival response rates compared monotherapy. Mechanisms clinical resistance to RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) whole-transcriptome (RNA-seq) on pretreatment drug-resistant tumors from five patients acquired dabrafenib/trametinib. In three these patients, we identified...
The tuberous sclerosis tumor suppressors TSC1 and TSC2 regulate the mTOR pathway to control translation cell growth in response nutrient factor stimuli. We have recently identified stress REDD1 gene as a mediator of complex (TSC)-dependent regulation by hypoxia. Here, we demonstrate that inhibits function energy stress. Endogenous is induced following stress, REDD1−/− cells are highly defective dephosphorylation key substrates S6K 4E-BP1 either ATP depletion or direct activation...
Tumor-specific genomic information has the potential to guide therapeutic strategies and revolutionize patient treatment. Currently, this approach is limited by an abundance of disease-associated mutants whose biological functions impacts on response are uncharacterized. To begin address limitation, we functionally characterized nearly all (99.84%) missense MAPK1/ERK2, essential effector oncogenic RAS RAF. Using approach, discovered rare gain- loss-of-function ERK2 found in human tumors,...
Abstract The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. different mutation spectra these diseases are reflected divergent responses to EGFR inhibition: significant patient benefit cancer, but limited glioblastoma. Here, we report a comprehensive mutational analysis of function. We perform saturation mutagenesis assess function ~22,500 variants human EGFR-dependent cell line. This...