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
4758 - A Phase I Study of the CDK4/6 Inhibitor, Palbociclib in combination with Cetuximab and Intensity Modulated Radiation Therapy (IMRT) for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN); A Result of Dose Escalation Cohort
Presenter: Nuttapong Ngamphaiboon
Session: Poster Display session 3
Resources:
Abstract
2607 - Single cycle induction treatment with Cisplatin/Docetaxel plus Durvalumab/Tremelimumab in Stage III-IVB head and neck squamous cell cancer (CheckRad-CD8 trial)
Presenter: Markus Hecht
Session: Poster Display session 3
Resources:
Abstract
1388 - Radiotherapy plus cisplatin (CDDP) or cetuximab (C225) in human papilloma-virus (HPV)-associated oropharyngeal cancer (OPC)? A dillema finally resolved. An updated meta-analysis.
Presenter: Petar Suton
Session: Poster Display session 3
Resources:
Abstract
1478 - Treatment outcomes of head and neck cancer patients 70 years and older receiving different chemo-radiation combinations.
Presenter: Majd Issa
Session: Poster Display session 3
Resources:
Abstract
3985 - Brachytherapy and non-cancer mortality in patients with oral cavity and oropharynx SCCs
Presenter: Jovian Yu
Session: Poster Display session 3
Resources:
Abstract
4036 - Final results of a phase II study of induction chemotherapy (CT) with paclitaxel (PTX) and panitumumab (P) followed by radiotherapy (RT) and P in patients (pts) with locally advanced head and neck cancer (LAHNC) no candidates to platinum: study PANTERA
Presenter: Javier Martinez Trufero
Session: Poster Display session 3
Resources:
Abstract
4779 - Window of Opportunity for Durvalumab (MEDI4736) plus Metformin Trial in Squamous Cell Carcinoma of the Head and Neck (SCCHN): interim safety analysis
Presenter: Tony Richa
Session: Poster Display session 3
Resources:
Abstract
2757 - Severe Oral Mucositis (SOM) Mitigation by Genetically Modified Lactococcus Lactis Bacteria (LLB) Producing Human Trefoil Factor 1 (hTFF1; AG013) in Patients Being Treated With Concomitant Chemoradiation (CRT) for Oral and Oropharyngeal Cancers (OCOPC)
Presenter: Suraj Singh
Session: Poster Display session 3
Resources:
Abstract
5559 - Transcriptome signatures of treatment responses in a preoperative window of opportunity trial of nivolumab and tadalafil in resectable squamous cell carcinoma of the head and neck
Presenter: Sanket Shukla
Session: Poster Display session 3
Resources:
Abstract
3263 - Risk and Impact of Renal Impairment of Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Who Received Chemoradiotherapy with Cisplatin
Presenter: Thana Patimarattananan
Session: Poster Display session 3
Resources:
Abstract