Published articles by founders lab
BRAF Colon Cancer
Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harbouring the same BRAF (V600E ) oncogenic lesion have poor prognosis and show only a very limited response to this dru To investigate the cause of the limited therapeutic effect of PLX4032 in BRAF (V600E ) mutant colon tumours, here we performed an RNA-interference- based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition.
sorafenib in NSCLC
The multikinase inhibitor sorafenib is under clinical investigation for the treatment of many solid tumors, but in most cases, the molecular target responsible for the clinical effect is unknown. Furthermore, enhancing the effectiveness of sorafenib using combination strategies is a major clinical challenge. Here, we identify sorafenib as an activator of AMP-activated protein kinase (AMPK), in a manner that involves either upstream LKB1 or CAMKK2. We further show in a phase II clinical trial in KRAS mutant advanced non-small cell lung cancer (NSCLC) with single agent sorafenib an improved disease control rate in patients using the antidiabetic drug metformin.
MEK resistance in kras mutant nsclc
There are no effective therapies for the ~30% of human malignancies with mutant RAS oncogenes. Using a kinome-centered synthetic lethality screen, we find that suppression of the ERBB3 receptor tyrosine kinase sensitizes KRAS mutant lung and colon cancer cells to MEK inhibitors. We show that MEK inhibition results in MYC-dependent transcriptional upregulation of ERBB3, which is responsible for intrinsic drug resistance. Drugs targeting both EGFR and ERBB2, each capable of forming heterodimers with ERBB3, can reverse unresponsiveness to MEK inhibition by decreasing inhibitory phosphorylation of the proapoptotic proteins BAD and BIM. Moreover, ERBB3 protein level is a biomarker of response to combinatorial treatment. These data suggest a combination strategy for treating KRAS mutant colon and lung cancers and a way to identify the tumors that are most likely to benefit from such combinatorial treatment.
Variable screen quality, off-target effects, and unclear false discovery rates often hamper large-scale functional genomic screens in mammalian cells. Hart et al (2014) introduce gold standard reference sets of essential and non-essential genes, aiming at standardizing the analysis of genome-wide screens. This work provides a framework to compare both the quality and analysis methods of functional genetic screens.
In the last decade, several screening technologies have been developed that allow for genome-scale perturbation of gene expression in mammalian cells. These include siRNA, shRNA, gene traps, and more recently CRISPR-based gene editing technologies. In particular, large-scale shRNA screens have been applied broadly to identify genes that are lethal under specific circumstances, for example in combination with a drug treatment or in the context of disease-specific genetic alterations. These context-specific essential genes could represent interesting new therapeutic targets. Unfortunately, results from such large-scale screens are often met with limited reproducibility and sensitivity, due to extensive off-target effects and variable knockdown efficiency. In addition, several analytical methods with different criteria for hit selection are in use, further complicating the interpretation and comparison of various screening efforts.