CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer.
Journal of Clinical Investigation 126(7):2610 (2016)
Small-cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with limited treatment options. CD47 is a cell-surface molecule that promotes immune evasion by engaging signal-regulatory protein alpha (SIRPα), which serves as an inhibitory receptor on macrophages. Here, we found that...
Telomerase activation by genomic rearrangements in high-risk neuroblastoma.
Nature 526(7575):700 (2015)
Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their mole...
Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach.
Journal of medicinal and pharmaceutical chemistry 58(17):6844 (2015)
Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong ...
Comprehensive genomic profiles of small cell lung cancer.
Nature 524(7563):47 (2015)
We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis...
A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer.
Cell 162(1):146 (2015)
KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell...
Spatial Tumor Heterogeneity in Lung Cancer with Acquired Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance: Targeting High-Level MET-Amplification and EGFR T790M Mutation Occurring at Different Sites in the Same Patient.
Journal of Thoracic Oncology 10(6):e40 (2015)
Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer.
Clinical Cancer Research 21(9):1989 (2015)
The four members of the ERBB (HER) family of transmembrane receptor tyrosine kinases are frequently activated in cancer by several mechanisms, such as mutation, amplification, or autocrine ligand-receptor stimulation. We recently identified gene fusions involving the ERBB ligand gene, NRG1, whic...
Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort.
Journal of Clinical Oncology 33(9):992 (2015)
Approximately 1% of lung adenocarcinomas are driven by oncogenic ROS1 rearrangement. Crizotinib is a potent inhibitor of both ROS1 and ALK kinase domains.
In the absence of a prospective clinical trial in Europe, we conducted a retrospective study in centers that tested for ROS1 rearrangement. E...
PD-L1 expression in small cell neuroendocrine carcinomas.
European Journal of Cancer 51(3):421 (2015)
Small cell lung cancer and extrapulmonary small cell carcinomas are the most aggressive type of neuroendocrine carcinomas. Clinical treatment relies on conventional chemotherapy and radiotherapy; relapses are frequent. The PD-1/PD-L1/PD-L2 pathway is a major target of anti-tumour immunotherapy. ...
Identification and further development of potent TBK1 inhibitors.
ACS Chemical Biology 10(1):289 (2015)
The cytosolic Ser/Thr kinase TBK1 was discovered to be an essential element in the mediation of signals that lead to tumor migration and progression. These findings meet the need for the identification of novel tool compounds and potential therapeutics to gain deeper insights into TBK1 related s...
Identification of novel fusion genes in lung cancer using breakpoint assembly of transcriptome sequencing data.
Genome Biology 16(1):7 (2015)
Genomic translocation events frequently underlie cancer development through generation of gene fusions with oncogenic properties. Identification of such fusion transcripts by transcriptome sequencing might help to discover new potential therapeutic targets. We developed TRUP (Tumor-specimen suit...
Era of comprehensive cancer genome analyses.
Journal of Clinical Oncology 32(36):4029 (2014)
Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer.
Nature Medicine 20(9):1027 (2014)
Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising...
CGARS: cancer genome analysis by rank sums.
Cancer genomes are characterized by the accumulation of point mutations and structural alterations such as copy-number alterations and genomic rearrangements. Among structural changes, systematic analyses of copy-number alterations have provided deeper insight into the architecture of cancer gen...
CD74-NRG1 fusions in lung adenocarcinoma.
Cancer Discovery 4(4):415 (2014)
We discovered a novel somatic gene fusion, CD74-NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucino...
Overcoming drug resistance in ALK-rearranged lung cancer.
New England Journal of Medicine 370(13):1250 (2014)
Cell-autonomous and non-cell-autonomous mechanisms of transformation by amplified FGFR1 in lung cancer.
Cancer Discovery 4(2):246 (2014)
The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplified in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplified tumors are also sensitive to fibroblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other re...
Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids.
Nature Communications 5:3518 (2014)
Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmo...
Targeting gain of function and resistance mutations in Abl and KIT by hybrid compound design.
Journal of medicinal and pharmaceutical chemistry 56(14):5757 (2013)
Mutations in the catalytic domain at the gatekeeper position represent the most prominent drug-resistant variants of kinases and significantly impair the efficacy of targeted cancer therapies. Understanding the mechanisms of drug resistance at the molecular and atomic levels will aid in the desi...
Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors.
Science Translational Medicine 5(189):189ra78 (2013)
When the integrity of the genome is threatened, cells activate a complex, kinase-based signaling network to arrest the cell cycle, initiate DNA repair, or, if the extent of damage is beyond repair capacity, induce apoptotic cell death. The ATM protein lies at the heart of this signaling network,...