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Simple Summary: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, with a heterogeneous characteristic. We firstly systematically screened the critical gene ubiquitin-specific protease 14 (USP14) in HNSCC from the DUB library after building a risk signature. Our data suggested that USP14 regulated heat shock transcription factor 1 (HSF1) stabilization by its deubiquitination and increased its downstream proteins, such as heat shock protein 60 (HSP60), HSP70, and HSP90, to promote HNSCC proliferation and lung metastasis in vivo and in vitro, and the overexpression of HSF1 reversed the inhibitory effect of USP14 depletion in vivo. Forty-five tissue samples from patients with HNSCC cancer were collected to determine the correlation of USP14 and HSF1 expression in the diagnosis of HNSCC, which is a novel mechanism of USP14 as a carcinogenic gene in HNSCC. Our results emphasized that USP14 and its downstream HSF1 have therapeutic potential in targeting HNSCC. The ubiquitin-proteasome system is a pivotal intracellular proteolysis process in posttranslational modification. It regulates multiple cellular processes. Deubiquitinating enzymes (DUBs) are a stabilizer in proteins associated with tumor growth and metastasis. However, the link between DUBs and HNSCC remains incompletely understood. In this study, therefore, we identified USP14 as a tumor proliferation enhancer and a substantially hyperactive deubiquitinase in HNSCC samples, implying a poor prognosis prediction. Silencing USP14 in vitro conspicuously inhibited HNSCC cell proliferation and migration. Consistently, defective USP14 in vivo significantly diminished HNSCC tumor growth and lung metastasis compared to the control group. Luciferase assays indicated that HSF1 was downstream from USP14, and an evaluation of the cellular effects of HSF1 overexpression in USP14-dificient mice tumors showed that elevated HSF1 reversed HNSCC growth and metastasis predominantly through the HSF1-HSP pathway. Mechanistically, USP14 encouraged HSF1 expression by deubiquitinating and stabilizing HSF1, which subsequently orchestrated transcriptional activation in HSP60, HSP70, and HSP90, ultimately leading to HNSCC progression and metastasis. Collectively, we uncovered that hyperactive USP14 contributed to HNSCC tumor growth and lung metastasis by reinforcing HSF1-depedent HSP activation, and our findings provided the insight that targeting USP14 could be a promising prognostic and therapeutic strategy for HSNCC. [ABSTRACT FROM AUTHOR]

The term "undruggable" is to describe molecules that are not targetable or at least hard to target pharmacologically. Unfortunately, some targets with potent oncogenic activity fall into this category, and currently little is known about how to solve this problem, which largely hampered drug research on human cancers. Ras, as one of the most common oncogenes, was previously considered "undruggable", but in recent years, a few small molecules like Sotorasib (AMG-510) have emerged and proved their targeted anti-cancer effects. Further, myc, as one of the most studied oncogenes, and tp53, being the most common tumor suppressor genes, are both considered "undruggable". Many attempts have been made to target these "undruggable" targets, but little progress has been made yet. This article summarizes the current progress of direct and indirect targeting approaches for ras, myc, two oncogenes, and tp53, a tumor suppressor gene. These are potential therapeutic targets but are considered "undruggable". We conclude with some emerging research approaches like proteolysis targeting chimeras (PROTACs), cancer vaccines, and artificial intelligence (AI)-based drug discovery, which might provide new cues for cancer intervention. Therefore, this review sets out to clarify the current status of targeted anti-cancer drug research, and the insights gained from this review may be of assistance to learn from experience and find new ideas in developing new chemicals that directly target such "undruggable" molecules. [ABSTRACT FROM AUTHOR]

Background: KRAS mutations are the most common oncogenic driver mutations of non-small cell lung cancer (NSCLC) in the Western world. Mutations of the KRAS gene are most prevalent in the patient population of current and former cigarette smokers. With the recent pivotal approval of a targeted inhibitor therapy for patients with KRAS p.G12C mutated and pretreated NSCLC, analysis of the heterogeneity of KRAS mutations and concomitant molecular alterations in patients with these tumors at all clinical stages is indicated. Methods: In this retrospective analysis, patient pathology records were reviewed for all cases receiving a pathologic diagnosis of NSCLC within our hospital system. All data were collected with IRB approval. Cases of indeterminate tumor type favoring a non-lung primary, as well as non-adenocarcinoma NSCLC (eg, squamous) were excluded from the cohort. In this hospital system, molecular testing for KRAS mutations is part of a molecular biomarker panel that is reflex ordered at initial diagnosis by the pathologist and may be performed as a single gene test or as a solid organ cancer hotspot panel by next generation sequencing. For each patient, KRAS mutational status and specific KRAS mutations, if present, were collated. Additional information assessed for this study included patient demographics (age, gender, and smoking history), tumor staging if available, PD-L1 expression levels by immunohistochemistry (IHC), and the presence of other genetic alterations (EGFR, ALK, and STK11). Results: Between January 1, 2017 and January 1, 2019, there were 276 patients diagnosed with NSCLC of all stages who had KRAS mutational analysis performed in our hospital system and who met the criteria for inclusion into the study cohort. A KRAS driver mutation was detected in 29% of these patients. The most frequently identified KRAS mutation was p.G12C (38%), followed by p.G12D (21%) and p.G12V (13%). KRAS- mutated lung adenocarcinoma was significantly associated with current or former patient smoking status in this cohort (29/202 (14%) smokers and 1/74 (1%) non-smokers; P =.0006). PD-L1 expression of at least 1% by IHC was present in 43% of KRAS -mutated lung adenocarcinomas and 45% of non- KRAS -mutated adenocarcinomas. In this study, KRAS mutations were not found to co-occur with gene alterations in EGFR, ALK, or STK11. In 48% of cases, at least one genetic alteration (KRAS, ALK, EGFR, or STK11) was identified. Conclusions: In this study cohort, KRAS -mutated lung adenocarcinoma demonstrated significant mutational heterogeneity, which is consistent with previously published studies. KRAS mutational status was also significantly associated with a current or former smoking history. Notably, p.G12C was the most frequently identified KRAS mutation in this cohort, with a frequency of 38%. This finding is particularly relevant given the recent approval of a KRAS p.G12C-specific targeted inhibitor therapy and the continued development of additional KRAS targeted therapies that may prove effective in treating NSCLC. These findings also highlight the necessity of considering molecular testing for KRAS mutations in patients with NSCLC and a smoking history, as this population most frequently harbors KRAS mutations and may benefit from these emerging targeted therapies. [ABSTRACT FROM AUTHOR]

BACKGROUND: KRAS mutations are the most common oncogenic driver mutations of non-small cell lung cancer (NSCLC) in the Western world. Mutations of the KRAS gene are most prevalent in the patient population of current and former cigarette smokers. With the recent pivotal approval of a targeted inhibitor therapy for patients with KRAS p.G12C mutated and pretreated NSCLC, analysis of the heterogeneity of KRAS mutations and concomitant molecular alterations in patients with these tumors at all clinical stages is indicated. METHODS: In this retrospective analysis, patient pathology records were reviewed for all cases receiving a pathologic diagnosis of NSCLC within our hospital system. All data were collected with IRB approval. Cases of indeterminate tumor type favoring a non-lung primary, as well as non-adenocarcinoma NSCLC (eg, squamous) were excluded from the cohort. In this hospital system, molecular testing for KRAS mutations is part of a molecular biomarker panel that is reflex ordered at initial diagnosis by the pathologist and may be performed as a single gene test or as a solid organ cancer hotspot panel by next generation sequencing. For each patient, KRAS mutational status and specific KRAS mutations, if present, were collated. Additional information assessed for this study included patient demographics (age, gender, and smoking history), tumor staging if available, PD-L1 expression levels by immunohistochemistry (IHC), and the presence of other genetic alterations (EGFR, ALK, and STK11). RESULTS: Between January 1, 2017 and January 1, 2019, there were 276 patients diagnosed with NSCLC of all stages who had KRAS mutational analysis performed in our hospital system and who met the criteria for inclusion into the study cohort. A KRAS driver mutation was detected in 29% of these patients. The most frequently identified KRAS mutation was p.G12C (38%), followed by p.G12D (21%) and p.G12V (13%). KRAS-mutated lung adenocarcinoma was significantly associated with current or former patient smoking status in this cohort (29/202 (14%) smokers and 1/74 (1%) non-smokers; P = .0006). PD-L1 expression of at least 1% by IHC was present in 43% of KRAS-mutated lung adenocarcinomas and 45% of non-KRAS-mutated adenocarcinomas. In this study, KRAS mutations were not found to co-occur with gene alterations in EGFR, ALK, or STK11. In 48% of cases, at least one genetic alteration (KRAS, ALK, EGFR, or STK11) was identified. CONCLUSIONS: In this study cohort, KRAS-mutated lung adenocarcinoma demonstrated significant mutational heterogeneity, which is consistent with previously published studies. KRAS mutational status was also significantly associated with a current or former smoking history. Notably, p.G12C was the most frequently identified KRAS mutation in this cohort, with a frequency of 38%. This finding is particularly relevant given the recent approval of a KRAS p.G12C-specific targeted inhibitor therapy and the continued development of additional KRAS targeted therapies that may prove effective in treating NSCLC. These findings also highlight the necessity of considering molecular testing for KRAS mutations in patients with NSCLC and a smoking history, as this population most frequently harbors KRAS mutations and may benefit from these emerging targeted therapies. [ABSTRACT FROM AUTHOR]

• Non-small cell lung cancer is heterogenous with many targetable driver mutations. • Tyrosine kinase inhibitors, monoclonal antibodies and conjugates are promising agents. • Targets include ROS1 , BRAF , NTRK , MET , uncommon EGFR , RET , HER2 , KRAS G12C and NRG1. • FDA approved agents include those targeting ROS1, BRAF V600E, NTRK, MET and RET. • Phase III trials testing ROS1, MET, EGFR, RET, HER2 and KRAS inhibitors are ongoing. Lung cancer is a highly heterogeneous disease often driven by well-characterized driver mutations. Although the best studied are common alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) oncogenes, rapid advances in molecular characterization has led to the development of novel therapeutics that inhibit additional oncogenic alterations in advanced NSCLC. The literature search identified 62 eligible phase I/II clinical trials or integrated analyses of assessing novel targeted agents against the following molecular alterations: ROS1 -rearranged, BRAF V600E-mutant, NTRK -rearranged, MET -altered, uncommon EGFR -mutant, RET -rearranged, HER2-positive, KRAS G12C-mutant and NRG1 -rearranged. This rapidly evolving field has produced many new targeted treatment options and promising outcomes have led to the FDA approval of seven novel agents for use in ROS1 -rearranged, BRAF V600E-mutant, NTRK -rearranged, MET exon 14 skipping-mutant or RET -rearranged advanced NSCLC. Research continues at a rapid pace, with a number of phase III trials underway to fully evaluate new promising agents under development for improving outcomes in patients with NSCLC harboring distinct molecular subtypes. This review will provide a comprehensive summary of existing data as well as a user-friendly guide on the current status of novel targeted therapy in oncogene-driven advanced NSCLC. [ABSTRACT FROM AUTHOR]

Inflammation is a driver of colorectal neoplasia; however, what particular inflammatory processes play a role in early carcinogenesis are unclear. We compared serum levels of 78 inflammation markers between 171 pathologically confirmed colorectal adenoma cases (including 48 incident cases) and 344 controls within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We used weighted multivariable logistic regression to compute odds ratio (OR) and 95% confidence interval (CI). We found 14 markers associated with risk of adenoma overall; three of these were also associated with incident adenoma: CC-chemokine cysteine motif chemokine ligand 20 (CCL20) [overall adenoma fourth versus first quartile: OR 4.8, 95% CI 2.0–12, P trend 0.0007; incident adenoma third versus first tertile: OR 4.6, 95% CI 1.0–22, P trend 0.03], growth-related gene oncogene products (GRO) [OR 3.8, 95% CI 1.6–9.3, P trend 0.006 and OR 3.6, 95% CI 1.1–12, P trend 0.04, respectively] and insulin [OR 2.9, 95% CI 0.8–10, P trend 0.05 and OR 7.8, 95% CI 1.3–46, P trend 0.03, respectively]. All statistical tests were two-sided. These results provide important new evidence implicating CCL20- and GRO-related pathways in early colorectal carcinogenesis and further support a role for insulin. [ABSTRACT FROM AUTHOR]

Technological advances applied to preclinical and clinical scientific research have significantly enabled the broadening of knowledge regarding neoplastic cells biology in the last two decades. The characterization of genetic and epigenetic alterations which are involved in carcinogenesis; the molecular subclassification of tumors; the understanding of normal and neoplastic cells interactions in the tumor microenvironment; and the description of molecular bases that explain the influence of factors such as exercise, diet and microbiota composition on cancer progression have contributed to support the importance of precision medicine in cancer. The present research reviews the so-called “hallmarks of cancer” and their “enabling characteristics”, i.e. those properties inherent to cancer cells that allow to evade intrinsic and extrinsic mechanisms of carcinogenesis control. This paper is a follow-up review of studies on cancer immunology that started with the presentation of the molecular and cellular bases of the anti-tumoral immune response, and will eventually focus on the manipulation of the relationship between the immune system and malignancies as a cancer treatment strategy. [ABSTRACT FROM AUTHOR]

High frequency of mortality in patients with pancreatic ductal adenocarcinoma (PDAC) is vastly associated with the invasive and metastatic nature of these cancer cells. Little is known about the factors involved in this invasive/metastatic process. The current challenge in the treatment of these patients is the lack of viable options besides gemcitabine. The aim of this study was to evaluate the role of PDZ-binding kinase (PBK)/T-LAK cell-originated protein kinase (TOPK) in invasive PDAC cells and to determine whether PBK/TOPK expression drives invasiveness in PDAC. Using gain-of-function and loss-of-function studies in established and patient-derived xenograft–PDAC cell lines, and examining patient-derived archival tissue samples, we demonstrate for the first time that PBK/TOPK is upregulated in pancreatic cancer and expression levels are closely associated with the invasive property of pancreatic cancer cells. Modulation of PBK/TOPK causally regulates the invasive ability of PDAC cells. We also demonstrate that two key players in metastatic invasion, matrix metalloproteinases-2 (MMP-2) and MMP-9 gelatinase activity and gene promoter activities, are regulated by PBK/TOPK. Moreover, we demonstrate for the first time that PBK/TOPK provides stability of an oncoprotein, c-MYC, which transcriptionally regulates MMP-2 and MMP-9 in these invasive PDAC cells. Our in vitro and in situ data corroborate that PBK/TOPK is closely associated with the invasive nature of PDAC and reveal a novel mechanism by which the metastatic behavior of human pancreatic cancer cells is regulated. These findings provide a rationale for targeting PBK/TOPK for the therapeutic intervention of invasive/metastatic pancreatic cancer in human. [ABSTRACT FROM AUTHOR]

Purpose: To determine the expression of prostate cancer antigen 3 (PCA3) gene in peripheral blood and urine sediments from patients with prostate cancer (PCa) and benign prostatic hyperplasia (BPH) and normal subjects. Materials and Methods: A total number of 48 patients [24 with biopsy proven prostate cancer (PCa) and 24 with benign prostate hyperplasia (BPH)] were studied. Twenty-four healthy individuals were also recruited as control group. After blood and urine sampling, total RNA was extracted and cDNA was synthesized. Expression of PCA3 gene was assessed by quantitative reverse transcription polymerase chain reaction. Results: Comparison of PCA3 gene expression between control and BPH groups indicated no statistically significant differences in both urine and blood samples. Patients with PCa demonstrated an increased PCA3 gene expression rate compared to control and BPH groups (10.64 and 7.17 folds, respectively). The rate of fold increased PCA3 gene expression in urine was 20.90, 20.90, and 20.35 in patients with PCa, BPH and normal subjects, respectively. Conclusion: Evaluation of PCA3 gene expression can be considered as a reliable marker for detection of PCa. Increased level of this marker in urine sediments is more sensitive than blood for distinguishing between cancerous and non-cancerous groups. [ABSTRACT FROM AUTHOR]

Immunoreceptor tyrosine-based activation motifs (ITAMs) are involved in the transduction of signals necessary for activation, differentiation, and survival in hematopoietic cells. Several viruses have been shown to encode ITAM-containing transmembrane proteins. Although expression of these viral proteins has in some cases been shown to transform nonhematopoietic cells, a causal role for a functional ITAM in this process has not been elucidated. To examine the potential transforming properties of ITAM-containing proteins, a recombinant protein consisting of ITAM-containing cytoplasmic regions of the B-cell antigen receptor was expressed in immortalized murine mammary epithelial and fibroblast cells. Mammary epithelial cells expressing this construct exhibited depolarized morphology in three-dimensional cultures. This transformed phenotype was characterized by a loss of anchorage dependence and hallmarks of epithelial to mesenchymal transition. Fibroblasts expressing this ITAM construct also lost contact inhibition and anchorage dependence. The transformed phenotype seen in both cell types was abrogated upon tyrosine to phenylalanine substitutions of the ITAMs. Inhibition of Syk tyrosine kinase, which associates with the ITAM, also prevented cell transformation. Our results indicate that expression of a nonviral ITAM-containing protein is sufficient for cell transformation. Despite lacking intrinsic enzymatic activity, ITAM-containing proteins can function as potent oncoproteins by scaffolding downstream mediators.Oncogene (2006) 25, 2748–2757. doi:10.1038/sj.onc.1209296; published online 12 December 2005 [ABSTRACT FROM AUTHOR]

[Display omitted] • NTRK fusions are the primary oncogenic driver of a broad range of adult and pediatric cancers. • Though rare, NTRK fusions represent an important clinically actionable target. • Larotrectinib was approved by the EMA for treatment of NTRK fusion-driven cancers. • This consensus offers guidance for testing and treatment of NTRK fusion cancers with larotrectinib, a pan-Trk-inhibitor. • Early screening of patients for NTRK fusions should be performed whenever possible. • Larotrectinib should be considered as early as appropiate in the treatment sequence. Fusions of NTRK (neurotrophic tyrosine receptor kinase) genes with 5′ partner genes can result in the expression of chimeric proteins that drive oncogenesis through ligand-independent kinase activation. Despite variable frequencies of NTRK fusions in different tumor types, the fact that they are common to a wide range of cancers raises the possibility of developing tumor-agnostic treatments specifically targeting NTRK fusion products, irrespective of tumor type. The first-generation Trk (tropomyosin receptor kinase) inhibitor, larotrectinib, was the first tumor-agnostic treatment of NTRK fusion-positive cancers in adults and children, to be approved in the European Union. This consensus, developed by a Belgian multidisciplinary expert panel, aims to highlight the unmet medical need associated to NTRK fusion-driven cancer treatment and, based on current knowledge of NTRK fusions and larotrectinib treatment outcome and safety, provide comprehensive guidance to oncologists regarding NTRK fusion-driven cancer diagnostics and the best use of larotrectinib in real-world clinical settings. [ABSTRACT FROM AUTHOR]