Abstract 3264
Background
A subgroup of MEK1 mutations in human tumors were recently described as RAF- and phosphorylation independent and as insensitive to currently clinically used allosteric MEK inhibitors. We established a novel cell line that carries a MEK1 mutation of this class (pGlu102_Lys104delinsGln) and tested a novel ATP competitive MEK inhibitor (MAP855) in this model. According to our knowledge this is the first patient derived cell line with this type of MEK mutation and the first spitzoid melanoma cell model.
Methods
PF130 cell line was established from the pleural effusion sample of a 37-year-old male patient with spitzoid melanoma. NGS was used for mutational analysis. Cells were treated either with allosteric MEK inhibitor selumetinib or with newly developed ATP competitive MEK inhibitor MAP855. We analyzed changes in cell number, cell cycle distribution and ERK activation after treatment in vitro. Furthermore, the in vivo tumorigenicity was tested by injecting the cells subcutaneously, intrapleurally or intravenously into female SCID mice.
Results
We found that ATP competitive MEK inhibitor MAP855 strongly decreased the viability of PF130 cells, while allosteric inhibitor selumetinib did not. Cell cycle analysis showed that MAP588 treatment could induce cell death in PF130 cells in a concentration dependent manner and slightly reduced the amount of cells in the S and the G2M phases. Furthermore, MAP855 was able to reduce ERK protein activation in PF130 cells effectively while selumetinib treatment had no effect. In vivo, intrapleurally injected cells established macroscopic tumors in the chest cavity after two months while intravenously and subcutaneously delivered cells showed limited growth.
Conclusions
We established a new cellular model of tumors with RAF- and phosphorylation independent MEK mutation. We found that recently developed ATP-competitive MEK inhibitor MAP855 is a potent inhibitor of these cells in vitro. The in vivo efficacy is currently under investigation. Furthermore, we describe here to the best of our knowledge the first patient derived spitzoid melanoma cell model to test both in vitro and in vivo novel therapeutic modalities.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Balazs Hegedus.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
4634 - Comparative molecular analyses between microsatellite stable BRAFV600E mutant colorectal cancers and BRAFV600E mutant melanomas.
Presenter: Mohamed Salem
Session: Poster Display session 3
Resources:
Abstract
4918 - HER2 inhibition in Aggressive Squamous Cell Carcinomas driven by a common MET Sema Domain Polymorphism
Presenter: Nur Afiqah Mohamed Salleh
Session: Poster Display session 3
Resources:
Abstract
2426 - ADAM9 as a target for lung cancer treatment
Presenter: Yuh-pyng Sher
Session: Poster Display session 3
Resources:
Abstract
5537 - Novel polyurea/polyurethane nanocapsules loaded with a tambjamine analog to improve cancer chemotherapy delivery and safety in lung cancer
Presenter: Marta Perez Hernandez
Session: Poster Display session 3
Resources:
Abstract
1597 - Discovery of Clinical Candidate DBPR112, a Furanopyrimidine-based Epidermal Growth Factor Receptor Inhibitor for the Treatment of Non-Small Cell Lung Cancer
Presenter: Hsing-pang Hsieh
Session: Poster Display session 3
Resources:
Abstract
3543 - Molecular characteristics in lung squamous cell carcinomas dependent on TP53 status – putative targets
Presenter: Vilde Haakensen
Session: Poster Display session 3
Resources:
Abstract
4111 - Comparison of molecular profiles between primary tumour and matched metastasis in non-small cell lung cancer
Presenter: Asuka Kawachi
Session: Poster Display session 3
Resources:
Abstract
4559 - Treatment with BLU-667, a potent and selective RET inhibitor, provides rapid clearance of ctDNA in Patients with RET-altered Non-Small Cell Lung Cancer (NSCLC) and Thyroid Cancer
Presenter: Giuseppe Curigliano
Session: Poster Display session 3
Resources:
Abstract
2501 - Triple MET/SRC/PIM inhibition in MET addicted tumors
Presenter: Ilaria Attili
Session: Poster Display session 3
Resources:
Abstract
5655 - Bioactivation of napabucasin triggers reactive oxygen species–mediated cancer cell death
Presenter: Fieke Froeling
Session: Poster Display session 3
Resources:
Abstract