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Lung Cancer Features, Treatment Clues Emerge From 'Omic Analysis of Difficult-to-Treat Subtype

NEW YORK – Members of the Clinical Proteomics Tumor Analysis Consortium have come up with a catalog of proteogenomic features for tumors from a difficult-to-treat lung cancer subtype called lung squamous cell carcinoma, uncovering potential treatment targets and alterations that may help in developing a fuller understanding of the disease.

"Patients with lung squamous cell cancer have very limited therapeutic options, and even modest success in understanding this disease could make a difference in people's lives," co-first and co-corresponding author Shankha Satpathy, a proteomics group leader at the Broad Institute, said in a statement. "We hope the research community, from basic scientists to practicing oncologists, will make use of this new resource for testing hypotheses, stimulating further research, and opening new data-driven avenues for clinical trial design that, in the long run, could benefit patients."

As they reported in Cell on Thursday, Satpathy and his colleagues used whole-genome sequencing, exome sequencing, RNA sequencing, small RNA sequencing, liquid chromatography with tandem mass spectrometry, array-based methylation profiling, and other approaches to assess genomic, proteomic, transcriptomic, and post-transcriptional modification features in 108 pre-treatment, primary LSCC tumor samples, along with almost as many matched normal samples from nearby sites in the lung.

In addition to tumor clusters corresponding with four LSCC molecular subtypes described in the past, the team discovered a previously unappreciated subtype that appears particularly prone to metastasis — tumors marked by an uptick in kinase pathway activity and epithelial-to-mesenchymal transition-related molecular features.

Besides recurrent alterations in the tumors — including potentially targetable gene duplications, expression shifts, or chromatin modification-related transcription factor changes — the team outlined alterations that are shared with, and distinct from, those found in other cancers such as lung adenocarcinoma and head and neck squamous cell carcinoma.

"Understanding which protein levels are impacted by copy number alterations, and how mutations impact protein expression and pathway activity, provides deeper insights into cancer biology," co-senior author Michael Gillette, a proteomics group leader and pulmonary and critical care medicine researcher affiliated with the Broad Institute and Massachusetts General Hospital, said in a statement. "Often those insights hint at unexplored therapeutic options, or at specific subpopulations that might benefit from specific treatments."

In a subset of LSCC tumors with higher-than-usual expression of the SOX2 transcription factor, for example, the investigators saw reliance on distinct alterations that may be more amenable to therapeutic targeting, including the EZH2 or LSD1 chromatin modifiers.

Their results revealed other molecular relationships, as well — from suspected driver mutations involving the NSD3 gene in tumors with tricky-to-target FGFR1 copy number changes, or high survivin protein levels in the LSCC tumors with damped-down p63 expression, to characteristic post-transcriptional modifications that may serve as biomarkers for treatment response in some LSCC patients.

Using immune signature data for the tumors, meanwhile, the team tracked down sets of tumors classified as immunologically "hot," "warm," or "cold," along with related molecular and phenotypic features that might portend response to available or upcoming immunotherapy treatments.

"A deeper understanding of the immune landscape of LSCC tumors could eventually lead to more effective immunotherapies and markers for patient stratification," co-senior author Bing Zhang, a molecular and human genetics researcher at Baylor College of Medicine, said in a statement.

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