An Unusual Presentation of Adult Intussusception.

Intussusception is a condition characterized by the invagination of a proximal segment of the intestine into a distal segment. In adults, intussusception is commonly associated with a lead point. The most alarming lead point is an obstructing malignancy. Here, we present the case of a 57-year-old woman with ileocolic intussusception secondary to colonic adenocarcinoma. The patient presented to the emergency department following an incidental finding of bradycardia, with a heart rate of around 40 beats per minute. She presented with several weeks of cramping, right lower quadrant abdominal pain, lightheadedness, fatigue, and palpitations. A computed tomography scan revealed ileocolic intussusception. After the placement of a semi-permanent right subclavian pacer, the patient underwent a right hemicolectomy. Surgical findings were consistent with ileocolic intussusception suspicious of being initiated by a mass in the right cecum involving the appendiceal orifice and ileocecal valve that invaded through the muscularis propria into subserosal tissue. The mass was resected and sent to pathology, where it was classified as stage II colonic adenocarcinoma. This case highlights a nonspecific presentation of intussusception that was only identified due to incidental bradycardia.

The deubiquitinase USP9X regulates RIT1 protein abundance and oncogenic phenotypes.

RIT1 is a rare and understudied oncogene in lung cancer. Despite structural similarity to other RAS GTPase proteins such as KRAS, oncogenic RIT1 activity does not appear to be tightly regulated by nucleotide exchange or hydrolysis. Instead, there is a growing understanding that the protein abundance of RIT1 is important for its regulation and function. We previously identified the deubiquitinase USP9X as a RIT1 dependency in RIT1-mutant cells. Here, we demonstrate that both wild-type and mutant forms of RIT1 are substrates of USP9X. Depletion of USP9X leads to decreased RIT1 protein stability and abundance and resensitizes cells to EGFR tyrosine kinase inhibitors. Our work expands upon the current understanding of RIT1 protein regulation and presents USP9X as a key regulator of RIT1-driven oncogenic phenotypes.

Acetylation-dependent regulation of BRAF oncogenic function.

Aberrant BRAF activation, including the BRAFV600E mutation, is frequently observed in human cancers. However, it remains largely elusive whether other types of post-translational modification(s) in addition to phosphorylation and ubiquitination-dependent regulation also modulate BRAF kinase activity. Here, we report that the acetyltransferase p300 activates the BRAF kinase by promoting BRAF K601 acetylation, a process that is antagonized by the deacetylase SIRT1. Notably, K601 acetylation facilitates BRAF dimerization with RAF proteins and KSR1. Furthermore, K601 acetylation promotes melanoma cell proliferation and contributes to BRAFV600E inhibitor resistance in BRAFV600E harboring melanoma cells. As such, melanoma patient-derived K601E oncogenic mutation mimics K601 acetylation to augment BRAF kinase activity. Our findings, therefore, uncover a layer of BRAF regulation and suggest p300 hyperactivation or SIRT1 deficiency as potential biomarkers to determine ERK activation in melanomas.

RAF-MEK-ERK pathway in cancer evolution and treatment.

The RAF-MEK-ERK signaling cascade is a well-characterized MAPK pathway involved in cell proliferation and survival. The three-layered MAPK signaling cascade is initiated upon RTK and RAS activation. Three RAF isoforms ARAF, BRAF and CRAF, and their downstream MEK1/2 and ERK1/2 kinases constitute a coherently orchestrated signaling module that directs a range of physiological functions. Genetic alterations in this pathway are among the most prevalent in human cancers, which consist of numerous hot-spot mutations such as BRAFV600E. Oncogenic mutations in this pathway often override otherwise tightly regulated checkpoints to open the door for uncontrolled cell growth and neoplasia. The crosstalk between the RAF-MEK-ERK axis and other signaling pathways further extends the proliferative potential of this pathway in human cancers. In this review, we summarize the molecular architecture and physiological functions of the RAF-MEK-ERK pathway with emphasis on its dysregulations in human cancers, as well as the efforts made to target the RAF-MEK-ERK module using small molecule inhibitors.