LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer.

The success of molecular therapies targeting specific metabolic pathways in cancer is often limited by the plasticity and adaptability of metabolic networks. Here we show that pharmacologically induced lipotoxicity represents a promising therapeutic strategy for the treatment of hepatocellular carcinoma (HCC). LXRα-induced liponeogenesis and Raf-1 inhibition are synthetic lethal in HCC owing to a toxic accumulation of saturated fatty acids. Raf-1 was found to bind and activate SCD1, and conformation-changing DFG-out Raf inhibitors could disrupt this interaction, thereby blocking fatty acid desaturation and inducing lethal lipotoxicity. Studies in genetically engineered and nonalcoholic steatohepatitis-induced HCC mouse models and xenograft models of human HCC revealed that therapies comprising LXR agonists and Raf inhibitors were well tolerated and capable of overcoming therapy resistance in HCC. Conceptually, our study suggests pharmacologically induced lipotoxicity as a new mode for metabolic targeting of liver cancer.

Association of DNA repair genes polymorphisms and mutations with increased risk of head and neck cancer: a review.

DNA repair mechanisms allow maintain genomic stability and proper functioning within the cells. Any aberrations may cause an increased risk of many diseases such as cancer. The most crucial risk factors for head and neck squamous cell carcinoma are behavioral factors, predominantly chronic exposure to tobacco, alcohol addiction, and infection with human papillomavirus or Epstein-Barr virus. These agents can induce DNA damage; therefore, cells must activate appropriate mechanisms in order to function correctly. Cancer cells are marked with genomic instability, which is associated with a greater tendency for the accumulation of a DNA damage and increased chemo- and radioresistance. Multiple studies have assessed the correlation of increased head and neck cancer (HNC) risk with polymorphism in the DNA repair genes. However, they suggest that interaction of DNA repair genes mutations with susceptibility to HNC depends on a patient's race and risk factors, especially tobacco smoking. Further identification of these sequence variations must be performed. In this review, we discuss the current knowledge about the DNA repair genes mutations and polymorphisms associated with the high risk of head and neck treatment.