Discovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K.

The CDK12 inhibitor SR-4835 promotes the proteasomal degradation of cyclin K, contingent on the presence of CDK12 and the CUL4-RBX1-DDB1 E3 ligase complex. The inhibitor displays molecular glue activity, which correlates with its enhanced ability to inhibit cell growth. This effect is achieved by facilitating the formation of a ternary complex that requires the small molecule SR-4835, CDK12, and the adaptor protein DDB1, leading to the subsequent ubiquitination and degradation of cyclin K.

The non-canonical target PARP16 contributes to polypharmacology of the PARP inhibitor talazoparib and its synergy with WEE1 inhibitors.

PARP inhibitors (PARPis) display single-agent anticancer activity in small cell lung cancer (SCLC) and other neuroendocrine tumors independent of BRCA1/2 mutations. Here, we determine the differential efficacy of multiple clinical PARPis in SCLC cells. Compared with the other PARPis rucaparib, olaparib, and niraparib, talazoparib displays the highest potency across SCLC, including SLFN11-negative cells.

Turning liabilities into opportunities: Off-target based drug repurposing in cancer.

Targeted drugs and precision medicine have transformed the landscape of cancer therapy and significantly improved patient outcomes in many cases. However, as therapies are becoming more and more tailored to smaller patient populations and acquired resistance is limiting the duration of clinical responses, there is an ever increasing demand for new drugs, which is not easily met considering steadily rising drug attrition rates and development costs. Considering these challenges drug repurposing is an attractive complementary approach to traditional drug discovery that can satisfy some of these needs.

Functional genomics screen with pooled shRNA library and gene expression profiling with extracts of identify potential pathways for therapeutic targets in head and neck squamous cell carcinoma.

Tumor suppression by the extracts of (neem) works via anti-proliferation, cell cycle arrest, and apoptosis, demonstrated previously using cancer cell lines and live animal models. However, very little is known about the molecular targets and pathways that neem extracts and their associated compounds act through. Here, we address this using a genome-wide functional pooled shRNA screen on head and neck squamous cell carcinoma cell lines treated with crude neem leaf extracts, known for their anti-tumorigenic activity.

Detection of High-Risk Human Papillomavirus in Oral Cavity Squamous Cell Carcinoma Using Multiple Analytes and Their Role in Patient Survival.

Purpose: Accurate detection of human papillomavirus (HPV) in oral cavity squamous cell carcinoma (OSCC) is essential to understanding the role of HPV in disease prognosis and management of patients. We used different analytes and methods to understand the true prevalence of HPV in a cohort of patients with OSCC with different molecular backgrounds, and we correlated HPV data with patient survival.

Methods: We integrated data from multiple analytes (HPV DNA, HPV RNA, and p16), assays (immunohistochemistry, polymerase chain reaction [PCR], quantitative PCR [qPCR], and digital PCR), and molecular changes (somatic mutations and DNA methylation) from 153 patients with OSCC to correlate p16 expression, HPV DNA, and HPV RNA with HPV incidence and patient survival.

Functional Proteomics and Deep Network Interrogation Reveal a Complex Mechanism of Action of Midostaurin in Lung Cancer Cells.

Lung cancer is associated with high prevalence and mortality, and despite significant successes with targeted drugs in genomically defined subsets of lung cancer and immunotherapy, the majority of patients currently does not benefit from these therapies. Through a targeted drug screen, we found the recently approved multi-kinase inhibitor midostaurin to have potent activity in several lung cancer cells independent of its intended target, PKC, or a specific genomic marker. To determine the underlying mechanism of action we applied a layered functional proteomics approach and a new data integration method.

A minimal set of internal control genes for gene expression studies in head and neck squamous cell carcinoma.

Selection of the right reference gene(s) is crucial in the analysis and interpretation of gene expression data. The aim of the present study was to discover and validate a minimal set of internal control genes in head and neck tumor studies. We analyzed data from multiple sources (in house whole-genome gene expression microarrays, previously published quantitative real-time PCR (qPCR) data and RNA-seq data from TCGA) to come up with a list of 18 genes (discovery set) that had the lowest variance, a high level of expression across tumors, and their matched normal samples.

A Minimal DNA Methylation Signature in Oral Tongue Squamous Cell Carcinoma Links Altered Methylation with Tumor Attributes.

Unlabelled: Oral tongue squamous cell carcinomas (OTSCC) are a homogenous group of aggressive tumors in the head and neck region that spread early to lymph nodes and have a higher incidence of regional failure. In addition, there is a rising incidence of oral tongue cancer in younger populations. Studies on functional DNA methylation changes linked with altered gene expression are critical for understanding the mechanisms underlying tumor development and metastasis.

Integrated analysis of oral tongue squamous cell carcinoma identifies key variants and pathways linked to risk habits, HPV, clinical parameters and tumor recurrence.

Oral tongue squamous cell carcinomas (OTSCC) are a homogeneous group of tumors characterized by aggressive behavior, early spread to lymph nodes and a higher rate of regional failure. Additionally, the incidence of OTSCC among younger population (<50yrs) is on the rise; many of whom lack the typical associated risk factors of alcohol and/or tobacco exposure. We present data on single nucleotide variations (SNVs), indels, regions with loss of heterozygosity (LOH), and copy number variations (CNVs) from fifty-paired oral tongue primary tumors and link the significant somatic variants with clinical parameters, epidemiological factors including human papilloma virus (HPV) infection and tumor recurrence.

Gene and miRNA expression changes in squamous cell carcinoma of larynx and hypopharynx.

Laryngo-pharyngeal squamous cell carcinomas are one of the most common head and neck cancers. Despite the presence of a large body of information, molecular biomarkers are not currently used in the diagnosis, treatment and management of patients for this group of cancer. Here, we have profiled expression of genes and microRNAs of larynx and hypopharynx tumors using high-throughput sequencing experiments.

High expression of survivin and its splice variants survivin ΔEx3 and survivin 2 B in oral cancers.

Objectives: We have previously reported inactivation of p53 in 46% of Indian patients with oral cancer. Survivin, a p53 target gene and an inhibitor of apoptosis protein (IAP), is overexpressed in several cancers, including oral cancers. Studies assessing the role of survivin and its splice variants in oral cancers are, however, rare.

Overexpression of Mcl-1L splice variant is associated with poor prognosis and chemoresistance in oral cancers.

Background: Altered expression of Mcl-1, an anti-apoptotic member of the Bcl-2 family, has been linked to the progression and outcome of a variety of malignancies. We have previously reported the overexpression of Mcl-1 protein in human oral cancers. The present study aimed to evaluate the clinicopathological significance of the expression of three known Mcl-1 isoforms in oral tumors and the effect of targeting Mcl-1L isoform on chemosensitivity of oral cancer cells.

Association of anti-apoptotic Mcl-1L isoform expression with radioresistance of oral squamous carcinoma cells.

Background: Oral cancer is a common cancer and a major health problem in the Indian subcontinent. At our laboratory Mcl-1, an anti-apoptotic member of the Bcl-2 family has been demonstrated to be overexpressed in oral cancers and to predict outcome in oral cancer patients treated with definitive radiotherapy. To study the role of Mcl-1 isoforms in radiation response of oral squamous carcinoma cells (OSCC), we investigated in the present study, the association of Mcl-1 isoform expression with radiosensitivity of OSCC, using siRNA strategy.