E. Teugels PhD

Novel therapeutic molecular targets in lung cancer: non-V600 mutant and mutant

In three sequential studies, we pre-clinically investigated several previously unexplored lung cancer-derived BRAF mutations as well as a HER3 mutation and their response to clinically available targeted therapeutics. During the FIELT I clinical study at UZ Brussel, in which 229 non-small-cell lung carcinoma patients were prospectively investigated at the genomic level, twelve patients (5.2%) were identified to harbour a BRAF mutation in their tumour and one patient found to harbour a novel HER3 mutation. As opposed to melanoma, 75% of these non-small-cell lung carcinoma-derived BRAF mutations were non-V600. RAF inhibitors have only been clinically developed against BRAF V600 mutations because of concerns of paradoxical effect in non-V600 mutant cancers. The status of non-V600 mutations with regards to BRAF inhibition effects was unknown. We functionally analysed thirteen of such tumour-derived BRAF non-V600 mutations and demonstrated that all types of BRAF mutations cause pathway activation and are sensitive to clinically relevant doses of a combination of type I RAF-inhibitor (dabrafenib) and that paradoxical pathway activation is abrogated by MEK-inhibition (trametinib). This entails that dual inhibition of non-V600 mutations is effective and safe. Further, we investigated the comparative efficacy of two modes of RAF inhibition (type I vs type II) in suppressing mutant BRAF-induced ERK signalling. Our preclinical findings in non-V600 BRAF expressing cellular models suggest that the type II RAF-inhibition (AZ628) has more potential than the type I RAF-inhibition (dabrafenib), both as single agent and combined with MEK inhibition in suppressing the ERK pathway independent of the BRAF mutation type. We also explored a novel somatic lung cancer-derived V855 HER3 mutation. Our study provided evidence for oncogenicity of V855 HER3 in a HER2 and ligand-dependent manner, in murine and human cell lines. Further, we showed that the given V855A HER3 mutation predicts sensitivity to the clinically available HER-targeting therapeutic afatinib. Our findings support the clinical investigation of non-V600 BRAF mutated lung or other cancers with dual RAF and MEK inhibition and HER3 mutant cancers with afatinib.

(BELG J MED ONCOL 2019;13(1):31–34)

O.10 THE DEUBIQUITINASE USP13 AS A NOVEL THERAPEUTIC CO-TARGET IN EGFR MUTANT NON-SMALL CELL LUNG CANCER

P.01 A LUNG CANCER-DERIVED CRAF MUTATION IS ERK PATHWAY ACTIVATING AND PREDICTS SENSITIVITY TO COMBINED TYPE II RAF AND MEK INHIBITION

O.03 Identification of candidate breast cancer predisposition genes by sequencing extended panel of 492 cancer associated genes in BRCA1/2 negative probands

O.04 Type II RAF inhibition causes superior ERK suppression compared to type I RAF inhibition in different BRAF mutant types recurrently found in lung cancer

O.10 USP13 as a novel co-target for EGFR targeted therapies in EGFR mutant non-small cell lung cancer

P.01 Targeting Polo-like kinase 1 and TRAIL enhances apoptosis in non-small cell lung cancer (NSCLC) cells