Abstract 875P
Background
There is an unmet need for novel targets and predictive biomarkers for head and neck squamous cell carcinoma (HNSCC) in the recurrent metastatic setting. Molecular subtypes assessed by transcriptomic data have been defined and correlations between basal subtype and response to EGFR blockage have been shown. To improve tumor subtyping, and define potential drug targets and predictive biomarkers, we performed proteomic and phosphoproteomic profiling of an extended set of HNSCC patient derived tumor models (PDX) that have been characterized for their response to multiple drug compounds and further evaluated treatment combinations.
Methods
64 HNSCC PDX tumors were analyzed by established Tandem Mass Tag (TMT)-based mass spectrometry workflow. Bioinformatic analysis was performed by integrating proteomics and phosphoproteomic with clinical annotation, drug response data, gene expression and mutation profiles of these tumors. More than 8,500 human proteins and 15,000 phosphosites were quantified across the 64 PDXs.
Results
NMF clustering on proteome and phosphoproteome levels resulted in three distinct clusters overlapping partly with RNA-based classification termed classical, mesenchymal, and basal subtypes. Differential expression analysis validated clinical biomarkers for human papillomavirus (HPV) status and highlighted additional proteins so far not connected to HNSCC. Interestingly, CDK4 expression was associated with HPV positive tumors, whereas the homolog kinase CDK6 was found to be upregulated in HPV-negative tumors belonging to the basal-like proteomic subtype. Dependency Map (DEPMAP) analysis validated that CDK6 has strong codependency with EGFR in cell lines derived from HNSCC. All evaluated models were treated with cetuximab and 25 PDX models with CDK4/6 inhibitor palbociclib as single agent treatment. Combined treatment of cetuximab and palbociclib was evaluated in EGFR resistant, CDK6 high expressing tumor models.
Conclusions
Integrative proteogenomic tumor analysis is a powerful tool for cancer classification, may predict the efficacy of targeted therapies more accurately and displays new subtype-specific druggable protein targets.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
BMBF.
Disclosure
K. Klinghammer: Financial Interests, Personal, Advisory Board: BMS, MSD; Financial Interests, Personal, Invited Speaker: Merck Sanofi, onkowissen, Biontech; Non-Financial Interests, Principal Investigator: AstraZeneca, gsk, Kura Oncol., MSD, Biontech; Non-Financial Interests, Advisory Board: DGHO, DKG, AIO. All other authors have declared no conflicts of interest.
Resources from the same session
922P - Dose expansion results of the bifunctional EGFR/TGFβ inhibitor BCA101 with pembrolizumab in patients with recurrent, metastatic head and neck squamous cell carcinoma
Presenter: Glenn Hanna
Session: Poster session 12
923P - Phase II trial evaluating the efficacy of pembrolizumab combined with vorinostat in patients with recurrent and/or metastatic head & neck squamous cell carcinoma – subgroup analysis of the PEVOsq basket trial
Presenter: Christophe Le Tourneau
Session: Poster session 12
924P - Polyfunctional HPV16-Specific T cell responses in subjects receiving PDS0101 and pembrolizumab combination treatment for recurrent/metastatic HPV16-positive head and neck squamous cell carcinoma (HNSCC)
Presenter: Kevin Harrington
Session: Poster session 12
925P - Treatment discontinuation of immune checkpoint blockade in patients with head and neck squamous cell carcinoma experiencing complete or nearly complete remission
Presenter: Konrad Klinghammer
Session: Poster session 12
926P - UK national real-world outcome data of first-line pembrolizumab treatment in head and neck squamous cell cancer (HNSCC)
Presenter: Ifigenia Vasiliadou
Session: Poster session 12
927P - Patients (pts) with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) treated with nivolumab (NIVO) in the first-line (1L) or later-line (2L+) settings in Germany: Updated results from the real-world HANNA study
Presenter: Boris Kubuschok
Session: Poster session 12
928P - Prognostic value of body composition and nutritional assessment in recurrent/metastatic squamous cell carcinoma of head and neck (R/M SCCHN) treated with immunotherapy (IO)
Presenter: Zara Vidales Sepulveda
Session: Poster session 12
930P - Platinum and taxane (PT) plus immunotherapy versus immunotherapy alone in patients with recurrent/metastatic (R/M) head and neck cancer (HNSCC)
Presenter: Marcelo Bonomi
Session: Poster session 12
931P - Early recurrence, time-to-recurrence, and recurrence patterns: Assessing their impact on survival outcomes in recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC) patients
Presenter: Pasvich Pitakpaiboonkul
Session: Poster session 12