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
5218 - Elevated driver mutational burden or number of perturbed pathways and poor response to abiraterone or enzalutamide in metastatic castration-resistant prostate cancer
Presenter: Bram De Laere
Session: Poster Display session 3
Resources:
Abstract
2452 - High proportion of multiple KRAS mutations in circulating tumor DNA and tumor tissue of pancreatic ductal adenocarcinoma
Presenter: Min Kyeong Kim
Session: Poster Display session 3
Resources:
Abstract
3328 - Biological difference of tumor mutational burden (TMB) and microsatellite instability (MSI) status in patients (pts) with somatic vs. germline BRCA1/2-mutated advanced gastrointestinal (GI) cancers using cell-free DNA (cfDNA) sequencing analysis in the GOZILA study
Presenter: Yasuyuki Kawamoto
Session: Poster Display session 3
Resources:
Abstract
3022 - Cell-Free DNA to Detect Focal Versus Non-Focal MET Amplification in Metastatic Colorectal Cancer Patients: Combined Analysis from Japan and the United States
Presenter: Mishima Saori
Session: Poster Display session 3
Resources:
Abstract
2833 - Presence of circulating tumor DNA in surgically resected renal cell carcinoma is associated with advanced disease and poor patient prognosis
Presenter: Andres Correa
Session: Poster Display session 3
Resources:
Abstract
1376 - Combined genomic and epigenomic assessment of cell-free circulating tumor DNA (cfDNA) for cancer diagnosis and recurrence-risk assessment in early-stage lung cancer
Presenter: Junghee Lee
Session: Poster Display session 3
Resources:
Abstract
4050 - DEMo: a prospective evaluation of a prognostic clinico-molecular composite score in NSCLC patients treated with immunotherapy.
Presenter: Arsela Prelaj
Session: Poster Display session 3
Resources:
Abstract
4727 - Bespoke circulating tumor DNA (ctDNA) analysis as a predictive biomarker in solid tumor patients (pts) treated with single agent pembrolizumab (P)
Presenter: Cindy Yang
Session: Poster Display session 3
Resources:
Abstract
3662 - Dynamic changes in whole-genome cell-free DNA (cfDNA) to identify disease progression prior to imaging in advanced solid tumors
Presenter: Andrew Davis
Session: Poster Display session 3
Resources:
Abstract
3817 - Evaluation of Microsatellite Instability Testing Through cell-free DNA sequencing
Presenter: Shile Zhang
Session: Poster Display session 3
Resources:
Abstract