Abstract 55P
Background
The driver mutation BrafV600E in human melanoma has been successfully targeted by vemuarfenib and successors. Since then vertical inhibition of the mitogen-activated protein (MAP)-kinase pathway by dual inhibition of B-Raf and MAP-kinase kinase (MEK)1/2 has been introduced in the therapy of advanced melanoma. Here we investigated in vitro inhibition of the guanine nucleotide exchange factor Son of Sevenless (SOS) by BAY293 in order to identify possible synergism with Braf or/and MEK1/2 inhibitors in human melanoma cell lines.
Methods
The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assays and wound healing assays were used to monitor viability, proliferation and migration in human melanoma cell lines from the early (WM35, WM278, and WM793b) and the metastatic growth phase (A375 and 518a2), all harbouring the driver mutation BrafV600E, but wild type NRAS. Apoptosis and kinase signalling were investigated by caspase assays and Western blot analyses.
Results
The SOS inhibitor BAY293 inhibited basal ERK1/2 phosphorylation in a dose dependent manner in human metastatic A375 and 518a2 melanoma cells. Importantly, viability was not affected in these cells following BAY293 exposure times below 24h. Longer incubation times enhanced cell death and reduced gap closure in a wound healing assay. Co-application of BAY293 with inhibitors of B-Raf and/or MEK1/2 augmented these effects significantly. Concomitantly, ERK1/2 phosphorylation was significantly reduced by these drug combinations. Similar effects were seen in early stage melanoma cells so that no stage dependent differences were observed.
Conclusions
While the SOS inhibitor BAY293 is not capable to substantially inhibit viability of melanoma cell lines, co-administration with vemuarfenib and trametinib augment cytotoxicity in an additive manner. Taken together these results are indicative for additivity in vertical inhibition of the MAP kinse pathway using BAY293 also in wild type RAS melanoma.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
63P - Role of EGFR-targeted therapy in the treatment of advanced and metastatic cervical cancers
Presenter: Abhishek Krishna
Session: Cocktail & Poster Display session
Resources:
Abstract
64P - Isothermal chemical KRAS denaturation assay for monitoring stability and inhibitors interactions
Presenter: Randa Mahran
Session: Cocktail & Poster Display session
Resources:
Abstract
65P - Influence of efflux and uptake transporters on the pharmacokinetics of the SYK inhibitors entospletinib and lanraplenib
Presenter: Nancy Loos
Session: Cocktail & Poster Display session
Resources:
Abstract
66P - Targeting allosteric sites on PDK-1 and PLK-1 with bioactive compounds from <italic>Daucus carota</italic> as a potential therapy for triple-negative breast cancer
Presenter: Kayode Raheem
Session: Cocktail & Poster Display session
Resources:
Abstract
67P - Molecular testing and treatment of patients with advanced solid tumors harboring an NTRK gene fusion: Interim results of the REALTRK registry
Presenter: Corinne Vannier
Session: Cocktail & Poster Display session
Resources:
Abstract
68P - Investigating CDK4/6 palbociclib resistance mechanisms in MCF7 breast cancer cell line
Presenter: Heloise Beutier
Session: Cocktail & Poster Display session
Resources:
Abstract
69P - Osimertinib is selective against NSCLC cells and modulates the multidrug-resistant phenotype in patient-derived cell cultures and co-cultures of NSCLC cells and fibroblasts
Presenter: Sofija Jovanović Stojanov
Session: Cocktail & Poster Display session
Resources:
Abstract
71P - Molecular Tumor Board at the European Institute of Oncology: An early Italian precision oncology experience
Presenter: Edoardo Crimini
Session: Cocktail & Poster Display session
Resources:
Abstract
72P - MDM alterations in patients with advanced or metastatic cancers
Presenter: Iwona Lugowska
Session: Cocktail & Poster Display session
Resources:
Abstract
73P - Automated detection of typical and atypical mitotic figures for improving survival prediction in breast cancer
Presenter: Saima Ben Hadj
Session: Cocktail & Poster Display session
Resources:
Abstract