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
1122 - Platelets from metastatic cancer patients have increased aggregation and activation
Presenter: Meera Chauhan
Session: Poster Display session 3
Resources:
Abstract
2671 - Luminal B breast cancer prognosis prediction by comprehensive analysis of Homeobox genes
Presenter: Ayako Nakashoji
Session: Poster Display session 3
Resources:
Abstract
2650 - Long non-coding RNA E2F4as promotes tumor progression and predicts patient prognosis in human ovarian cancer
Presenter: Sun-Ae Park
Session: Poster Display session 3
Resources:
Abstract
1462 - FGF19 promotes esophageal squamous cell carcinoma progression by inhibiting autophagy
Presenter: Lisha Ying
Session: Poster Display session 3
Resources:
Abstract
5787 - Proof of concept on the role of ex vivo lung cancer spheroids, cytokines expression and PBMCs profiling in monitoring disease history and response to treatments.
Presenter: Raimondo Di Liello
Session: Poster Display session 3
Resources:
Abstract
5253 - Circulating microRNAs related to DNA damage response as predictors of survival in metastatic non- small cell lung cancer patients treated with platinum-based chemotherapy
Presenter: Dimitris Mavroudis
Session: Poster Display session 3
Resources:
Abstract
5286 - Prognostic value of CTCs in advanced NSCLC patients treated with platinum-based chemotherapy
Presenter: Silvia Calabuig-Fariñas
Session: Poster Display session 3
Resources:
Abstract
5781 - Exosomes in NSCLC as a source of biomarkers
Presenter: Elena Duréndez
Session: Poster Display session 3
Resources:
Abstract
1447 - The role of Pim-1 in the development and progression of papillary thyroid carcinoma
Presenter: Xin Zhu
Session: Poster Display session 3
Resources:
Abstract
1323 - Development and Validation of a RNA-Seq Based Prognostic Signature in Neuroblastoma
Presenter: Jian-Guo Zhou
Session: Poster Display session 3
Resources:
Abstract