The incidence of human papillomavirus (HPV) associated head and neck squamous cell carcinoma (HNSCC) has dramatically increased in recent decades. There is clear evidence in literature that patients with HPV-positive HNSCC have a significantly better prognosis after genotoxic therapies compared to those with HPV-negative HNSCC. This favorable outcome has been associated with distinct features in DNA damage repair (DDR) functions specific to HPV-positive HNSCC. As a result, weaknesses in DDR have been identified for both HPV-positive and HPV-negative HNSCC, respectively. Therefore, personalized therapy targeting the vulnerable aspects of DDR pathways based on HPV status and mutational profiles has been proposed for precise treatment of HNSCC patients. This review focuses on the most recent evidence regarding the impact of HPV on DDR pathways and the related therapeutic strategies in HNSCC. We anticipate that future translation of these discoveries into clinical practice may lead to treatment de-escalation approaches in HPV-positive HNSCC and more effective therapies for the poor prognosis HPV-negative HNSCC.
BRAF V600E is a constitutive BRAF (B-raf proto-oncogene, serine/threonine kinase) mutation that accounts for more than 90% of BRAF mutations in melanoma. Vemurafenib is a BRAF V600E selective kinase inhibitor (BRAFi) that is commonly used to treat BRAF V600E melanoma patients. However, vemurafenib treatment-induced resistance occurs in about 50% of patients diagnosed with melanoma, and half of the patients have disease progression within six months. But the mechanism and the consequences of BRAF inhibitor resistance have not been fully elucidated. In this review, we summarize the mechanism and the consequences of BRAF inhibitor vemurafenib resistance in melanoma, aiming to provide a guidance for the intervention of BRAF inhibitor resistance.
The accurate transmission of genetic information is crucial for the reproduction and evolution of life. To ensure the faithful transmission of genetic information from parents to offspring, organisms have developed a precise DNA replication regulation system. In eukaryotes, during the G1 phase of the cell cycle, the Origin Recognition Complex (ORC) firstly recognizes the specific regions on the chromosome, and then recruits CDC6, CDT1 and MCM complex to form a pre-replication complex (pre-RC), which marks the replication origins. As the cells enter the S phase, the replication origins are selectively activated. The correct selection and activation of DNA replication origins are of utmost importance for the process of DNA replication. Here we describe the processes involved in the selection and activation of replication origins, as well as the epigenetic regulation mechanisms of DNA replication initiation in eukaryotic organism, with a particular focus on histone variants and modifications.
Cancer occurs when a portion of the body's cells begin to divide uncontrollably and spread into surrounding tissues. Most common reason for growth is genetic mutations. DNA Double Strand Breaks (DSB) brought about by ionizing radiation or other cancer-causing chemicals are one of the unavoidable changes bringing about carcinogenesis. Efficient DNA repair is generally gainful for living beings but in cancer therapy efficient DNA repair challenges the activity of radio and chemotherapies based on DNA damaging agents with cells becoming resistant to drugs. DSB repair pathways therefore serve as critical components for tumor suppression. Cells accomplish error-free repair of DNA DSBs by homologous recombination (HR) repair pathway. Mammalian proteins involved in HR include BRCA1, BRCA2, RAD51 and the RAD51 paralogs. Targeting the function of these proteins can, therefore, offer solution to resistance to anti-cancer treatment, thereby improving the efficiency of chemotherapy and preventing reoccurrence of tumors. RAD51 and its paralogs are central players of the pathway and are targeted for functional disruption. Sequence analysis of RAD51 proteins demonstrates regions within the ATPase domain that are conserved across species and amongst various paralogs. Multiple CHK1/CHK2 phosphorylation sites are present in all the paralogs with at least one of the site in close proximity to the ATPase domain. Inhibitors are identified that bind to the ATP-binding pocket of RAD51 paralogs thereby affecting its hydrolysis. The RAD51 protein interaction with BRCA2 protein is another important target through peptides designed against evolutionarily conserved regions of BRCA2, BRC4. Combinatorial targeting of the function of proteins involved in HR in combination with DNA damaging agents can, therefore, offer solution to radio and chemoresistance, thereby improving the efficiency of chemotherapy and preventing re-occurrence of tumors.