Protein Biomarkers in Lung Cancer Screening: Technical Considerations and Feasibility Assessment.

Lung cancer remains the leading cause of cancer-related deaths worldwide, mainly due to late diagnosis and the presence of metastases. Several countries around the world have adopted nation-wide LDCT-based lung cancer screening that will benefit patients, shifting the stage at diagnosis to earlier stages with more therapeutic options. Biomarkers can help to optimize the screening process, as well as refine the TNM stratification of lung cancer patients, providing information regarding prognostics and recommending management strategies. Moreover, novel adjuvant strategies will clearly benefit from previous knowledge of the potential aggressiveness and biological traits of a given early-stage surgically resected tumor. This review focuses on proteins as promising biomarkers in the context of lung cancer screening. Despite great efforts, there are still no successful examples of biomarkers in lung cancer that have reached the clinics to be used in early detection and early management. Thus, the field of biomarkers in early lung cancer remains an evident unmet need. A more specific objective of this review is to present an up-to-date technical assessment of the potential use of protein biomarkers in early lung cancer detection and management. We provide an overview regarding the benefits, challenges, pitfalls and constraints in the development process of protein-based biomarkers. Additionally, we examine how a number of emerging protein analytical technologies may contribute to the optimization of novel robust biomarkers for screening and effective management of lung cancer.

DSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity.

Lung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-α-mediated CD8+-killing and immune-resistant lung tumors to anti-PD-1 treatment. Finally, in a series of lung cancer patients, DSTYK copy number gain predicts lack of response to the immunotherapy. In summary, we have uncovered DSTYK as new therapeutic target in lung cancer. Prioritization of this novel target for drug development and clinical testing may expand the percentage of NSCLC patients benefiting from immune-based treatments.

YES1 Is a Druggable Oncogenic Target in SCLC.

INTRODUCTION: SCLC is an extremely aggressive subtype of lung cancer without approved targeted therapies. Here we identified YES1 as a novel targetable oncogene driving SCLC maintenance and metastasis. METHODS: Association between YES1 levels and prognosis was evaluated in SCLC clinical samples. In vitro functional experiments for proliferation, apoptosis, cell cycle, and cytotoxicity were performed. Genetic and pharmacologic inhibition of YES1 was evaluated in vivo in cell- and patient-derived xenografts and metastasis. YES1 levels were evaluated in mouse and patient plasma-derived exosomes. RESULTS: Overexpression or gain/amplification of YES1 was identified in 31% and 26% of cases, respectively, across molecular subgroups, and was found as an independent predictor of poor prognosis. Genetic depletion of YES1 dramatically reduced cell proliferation, three-dimensional organoid formation, tumor growth, and distant metastasis, leading to extensive apoptosis and tumor regressions. Mechanistically, YES1-inhibited cells revealed alterations in the replisome and DNA repair processes, that conferred sensitivity to irradiation. Pharmacologic blockade with the novel YES1 inhibitor CH6953755 or dasatinib induced marked antitumor activity in organoid models and cell- and patient-derived xenografts. YES1 protein was detected in plasma exosomes from patients and mouse models, with levels matching those of tumors, suggesting that circulating YES1 could represent a biomarker for patient selection/monitoring. CONCLUSIONS: Our results provide evidence that YES1 is a new druggable oncogenic target and biomarker to advance the clinical management of a subpopulation of patients with SCLC.

Two cell line models to study multiorganic metastasis and immunotherapy in lung squamous cell carcinoma.

There is a paucity of adequate mouse models and cell lines available to study lung squamous cell carcinoma (LUSC). We have generated and characterized two models of phenotypically different transplantable LUSC cell lines, i.e. UN-SCC679 and UN-SCC680, derived from A/J mice that had been chemically induced with N-nitroso-tris-chloroethylurea (NTCU). Furthermore, we genetically characterized and compared both LUSC cell lines by performing whole-exome and RNA sequencing. These experiments revealed similar genetic and transcriptomic patterns that may correspond to the classic LUSC human subtype. In addition, we compared the immune landscape generated by both tumor cells lines in vivo and assessed their response to immune checkpoint inhibition. The differences between the two cell lines are a good model for the remarkable heterogeneity of human squamous cell carcinoma. Study of the metastatic potential of these models revealed that both cell lines represent the organotropism of LUSC in humans, i.e. affinity to the brain, bones, liver and adrenal glands. In summary, we have generated valuable cell line tools for LUSC research, which recapitulates the complexity of the human disease.