Articles

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

BJMO - volume 13, issue 1, february 2019

A. Noeparast PhD, I. Umelo , E. Teugels PhD, J. De Grève MD, PhD

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)

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

BJMO - 12, issue 3, february 2018

A. Noeparast PhD, J. De Grève MD, PhD, S. De Brakeleer PhD, P. Giron , C. Eggermont , Rajendra Bahadur Shahi , E. Teugels PhD

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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

BJMO - 2017, issue 3, february 2017

A. Noeparast PhD, P. Giron , S. De Brakeleer PhD, U. De Ridder , E. Teugels PhD, J. De Grève MD, PhD

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