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
3628 - Predictive model for survival in advanced non-small-cell lung cancer (NSCLC) treated with frontline pembrolizumab
Presenter: Xabier Mielgo Rubio
Session: Poster Display session 3
Resources:
Abstract
5705 - External validation and longitudinal extension of the LIPI (Lung Immune Prognostic Index) for immunotherapy outcomes in advanced non-small cell lung cancer.
Presenter: Jakob Riedl
Session: Poster Display session 3
Resources:
Abstract
5758 - Changes of TCR Repertoire in Metastatic Renal Cell Carcinoma and Metastatic Melanoma Patients Treated with Nivolumab
Presenter: Martin Klabusay
Session: Poster Display session 3
Resources:
Abstract
1743 - Expression of MHC class I, HLA-A and HLA-B identifies immune activated breast tumors with favorable outcome
Presenter: María Del Mar Noblejas López
Session: Poster Display session 3
Resources:
Abstract
2219 - Prognostic Significance of Tumor Tissue NeuGcGM3 Ganglioside Expression and Predictive Value of Circulating Tumor Cell Count Monitoring in Patients Receiving Racotumomab Immunotherapy
Presenter: Necdet Üskent
Session: Poster Display session 3
Resources:
Abstract
2996 - Evolution of Myeloid-Derived Suppressor Cells and Objective Response Rate in Relapsed/Refractory Diffuse Large B Cell Lymphoma (R/R DLBCL) patients after receiving immunotherapy
Presenter: Carlos Jiménez Cortegana
Session: Poster Display session 3
Resources:
Abstract
2110 - A Phase Ia/Ib trial of the anti-programmed death-ligand 1 (PD-L1) human monoclonal antibody (mAb), CS1001, in patients (pts) with advanced solid tumors or lymphomas
Presenter: Lin Shen
Session: Poster Display session 3
Resources:
Abstract
3515 - Results from a randomised Phase 1/2 trial evaluating the safety and antitumour activity of anti-PD-1 (MEDI0680)/anti-PD-L1 (durvalumab) vs anti-PD-1 (nivolumab) alone in metastatic clear cell renal cell carcinoma (ccRCC)
Presenter: Martin Voss
Session: Poster Display session 3
Resources:
Abstract
3566 - Pembrolizumab in Advanced Rare Cancers
Presenter: Aung Naing
Session: Poster Display session 3
Resources:
Abstract
3567 - High clinical benefit rates of pembrolizumab in very rare sarcoma histotypes: first results of the AcSé Pembrolizumab study
Presenter: Jean-Yves Blay
Session: Poster Display session 3
Resources:
Abstract