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Proteogenomic Analysis Uncovers HNSCC Subtypes, Possible Treatment Approaches

NEW YORK – A new study suggests that proteogenomic analyses may be able to match HPV-negative head and neck squamous cell carcinoma subtypes to potential treatment approaches.

Head and neck squamous cell carcinoma (HNSCC) affects about 53,000 people a year in the US, and though some targeted therapies like EGFR monoclonal antibody and PD-1 inhibitor treatments have been approved to treat HNSCC, response rates have been modest. 

By combining genomic, transcriptomic, and proteomic approaches, a Baylor College of Medicine-led team of researchers characterized more than 100 HPV-negative HNSCCs with the aim of determining the functional effects of the genomic alterations present in the cancer samples. As they reported on Thursday in Cancer Cell, the researchers identified molecular subtypes of HPV-negative HNSCC that could be susceptible to CDK inhibitor, anti-EGFR antibody, or immunotherapy treatments.

"Therapeutic hypotheses generated from this study may serve as the basis for future preclinical studies and clinical trials toward molecularly guided precision treatment of HPV-negative HNSCC," senior author Bing Zhang, a professor of molecular and human genetics at BCM, said in an email.

He and his colleagues collected tumor and matched blood or normal tissue samples from 108 people with treatment-naive, HPV-negative HNSCC for molecular profiling. They conducted exome, whole-genome, and RNA-sequencing analyses, as well as methylation analysis and proteomic and phosphoproteomic analyses and more to create a catalog of copy-number changes, protein and phosphosite alterations, and other mutations associated with HNSCC. 

An unsupervised clustering analysis grouped the tumors into three subtypes that overlapped with previously identified transcriptome-based HNSCC subtypes. But through their proteogenomic analyses, the researchers connected these three subtypes to approved drugs for HNSCC or to ones that are under investigation.

The researchers noted that, currently, EGFR amplification or overexpression is a poor predictor of response to EGFR monoclonal antibody treatment in HNSCC. Their analysis instead suggests that EGFR ligand abundance may be a better biomarker of which patients may respond to EGFR monoclonal antibody treatment, as tumors with high EGFR amplification do not necessarily have high levels of EGFR ligands — suggesting the ligands are the limited factor for activating the EGFR pathway and thus treatment response.

Additionally, the researchers found that the phosphorylation status of Rb might be a better measure of whether HNSCC might respond to CDK4/6 inhibitor therapy. They found that genomic or transcriptomic markers alone were not enough to gauge CDK4/6 activity, but that Rb phosphorylation status combined with CCND1/CDKN2A genomic alterations could serve as biomarkers for considering CDK4/6 inhibitor therapy.

The immune environments of HNSCC tumors could also indicate whether they may respond to immunotherapies, the researchers found. However, they noted that tumors with high expression levels of PD-L1 also tended to have higher expression levels of other immune checkpoint genes, possibly explaining low immunotherapy success rates. Their findings suggest that treatment of such immune-hot tumors with PD-L1 inhibitors might not be effective unless deployed in combination with other immunotherapies.

At the same time, they noted that immune-cold tumors are not good candidates for immunotherapies.

"We found three subtypes of head and neck squamous cell carcinoma, and each subtype may be good candidates for a different type of therapy — EGFR inhibitors, CDK inhibitors, or immunotherapy," Zhang said in a statement. "We also identified candidate biomarkers that could be used to match patients to effective therapies or clinical trials."

He added in an email that he and his colleagues are interested in next working with clinicians and pharmaceutical companies to test the hypotheses their findings have raised.