A study using proteogenomics has offered new insight into matching cancer patients with an effective therapy for their particular cancer.
Head and neck squamous cell carcinoma
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common epithelial malignancy in the world. It can be broadly classified into human papillomavirus (HPV)-associated (HPVpos) and HPV-negative (HPVneg) subtypes. HPVneg HNSCCs account for 75% of all HNSCCs and are associated with a worse prognosis compared with HPVpos tumours. Most patients are treated with surgery, chemotherapy and radiotherapy. Despite approval of targeted agents, such as EGFR mAbs and PD-1 inhibitors, overall response rates have been moderate. A complete understanding of how genetic aberrations drive tumour phenotypes also remains elusive. Most importantly, translation of genomic and transcriptomic findings into improved HNSCC treatment has been limited.
In a study, published in Cancer Cell, in order to understand how genetic aberrations drive tumour behaviour and response to therapies, researchers performed an integrated proteogenomics characterisation of 108 HPVneg HNSCCs. Specifically, they integrated mass spectrometry (MS)-based proteomics with genomics and transcriptomics.
Proteogenomics analysis
One important finding was that EGFR ligands, instead of EGFR itself, act as the limiting factor for the activation of EGFR pathways. In other words, when the ligand is in low abundance, the downstream pathway will not be triggered even if the protein is overexpressed. Therefore, the team proposed that the EGFR ligand should be used as a biomarker, rather than EGFR amplification or overexpression, to help select patients for the EGFR monoclonal antibody treatment.
Additionally, when tracking Rb (retinoblastoma), the team found that Rb phosphorylation status could potentially be a better indicator for patient’s response to CDK4/6 inhibitor therapy. They found that many mutations in the gene regulating CDK4/6 activity were neither necessary nor sufficient for activation of CDK4/6. The team found that the CDK4 activity was best measured through Rb phosphorylation measurements.
The team also gained important insights into the effectiveness of immunotherapy. For example, the researchers examined tumours with high expression of PD-L1. They found that when a tumour overexpressed PD-L1 it also upregulated other immune checkpoints. This enabled tumour growth despite the use of PD-1 inhibitors. This observation suggests that tumours with hot immune environments may require multiple types of immunotherapy. On the other hand, tumours with cold immune environments are not good targets for immunotherapy. This stems from problems with the antigen presentation pathway where multiple key gene components were found to be deleted.
These findings extend our understanding of HPVneg HNSCCs. It also generates potential therapeutic hypotheses that may form the basis of future studies or clinical trials for more molecularly driven treatments.
Image credit: By kjpargeter – www.freepik.com
