Abstract 5259
Background
Targeted therapy in melanoma has been a great success in extending progression free survival and overall survival for melanoma patients. These include BRAF inhibitors for patients with a BRAF V600 mutation and MEK inhibitors for patients with an NRAS G12 or Q61 mutation. However, only about 50 % of patients respond to single BRAF inhibitor therapy and about 70% respond to combination BRAF and MEK inhibitor therapy.
Methods
We in vitro tested each cell line for resistance to BRAF inhibitor and found 27 to be resistant. To elucidate the possible resistance mechanisms, we performed RNAseq and targeted panel sequencing on all 53 cultures and found specific subgroups of gene expression and mutations that define the innate and adaptive resistance populations.
Results
Surprisingly, a few melanoma cultures from patients who have never been exposed to BRAF inhibitors had innate resistance, while the majority of cell cultures from progressive patients were resistant to in vitro BRAF inhibition. . One surprising finding was that the phenotype switching signature was one of the resistant mechanisms in common for innate and adaptive resistance, suggesting a selection process for resistant cells during therapy. We also found mechanisms of resistance specific for adaptive resistance, there were many samples that gain mutations in NRAS or acquired a splicing event in BRAF that was not seen in the untreated tumor suggesting a de novo mechanism to resistance.
Conclusions
Overall, we noticed several mechanisms to innate and adaptive resistance which highlights tumor and patient heterogeneity when treated with BRAF inhibitors and reinforces the concept for precision medicine in the treatment of melanoma.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
EU Horizon 2020 PHC grant No. 633974 (SOUND – Statistical multi-Omics UNDerstanding of Patient Samples).
Disclosure
R. Dummer: Honoraria (self): Novartis; Honoraria (self): Merck Sharp & Dhome; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Roche; Honoraria (self): Amgen; Honoraria (self): Takeda; Honoraria (self): Pierre Fabre; Honoraria (self): Sun Pharma; Honoraria (self): Sanofi. All other authors have declared no conflicts of interest.
Resources from the same session
2316 - A 3D co-culture platform of breast cancer and patient derived immune cells to analyse the response to chemotherapy and immunotherapies
Presenter: Diana Saraiva
Session: Poster Display session 3
Resources:
Abstract
4290 - Characterization of the mechanism of action and efficacy of MEN1611 (PA799), a novel PI3K inhibitor, in breast cancer preclinical models.
Presenter: Alessio Fiascarelli
Session: Poster Display session 3
Resources:
Abstract
2167 - Neat-1: culprit lnRNA tying PIG-C, MSLN, CD80 in TNBC
Presenter: Nada Hussein
Session: Poster Display session 3
Resources:
Abstract
1829 - A novel RAF/MEK inhibitor CH5126766 in phase 1 clinical trial has an effectiveness in the combination with eribulin for the treatment of triple negative breast cancer
Presenter: Hisako Ono
Session: Poster Display session 3
Resources:
Abstract
4357 - Identification of a stemness-related gene panel associated with BET inhibition in triple negative breast cancer
Presenter: Eva Galan-Moya
Session: Poster Display session 3
Resources:
Abstract
5163 - Preclinical Evaluation targeting both IGF1R and IR in Triple Negative Breast Cancer
Presenter: Alex Eustace
Session: Poster Display session 3
Resources:
Abstract
832 - Monospecific antibody targeting of CDH11 inhibits epithelial-to-mesenchymal transition and represses cancer stem cell-like phenotype by up-regulating miR-335 in metastatic breast cancer, in vitro and in vivo.
Presenter: Jia-Hong Chen
Session: Poster Display session 3
Resources:
Abstract
3781 - Pharmacological screening with Chk1 inhibitors identify synergistic agents to overcome resistance to platinums in basal breast and ovarian cancer
Presenter: Ana Lucia Sanabria
Session: Poster Display session 3
Resources:
Abstract
3275 - Comparison of 11 circulating miRNAs and CA125 kinetics in ovarian cancer during first line treatment: data from the randomized CHIVA trial (a GINECO-GCIG study)
Presenter: Patrick Robelin
Session: Poster Display session 3
Resources:
Abstract
3391 - Inhibiting Ehmt2 and Ezh2 histone methyltransferases alters the immune microenvironment in a Trp53-/- murine ovarian cancer model
Presenter: Pavlina Spiliopoulou
Session: Poster Display session 3
Resources:
Abstract