5‐Fluorouracil preferentially sensitizes mutant KRAS non‐small cell lung carcinoma cells to TRAIL‐induced apoptosis

Abstract

Mutations in the KRAS gene are very common in non-small cell lung cancer (NSCLC), but effective therapies targeting KRAS have yet to be developed. Interest in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent inducer of cell death, has increased following the observation that TRAIL can selectively kill a wide variety of human cancer cells without killing normal cells both in vitro and in xenograft models. However, results from clinical trials of TRAIL-based therapy are disappointingly modest at best and many have demonstrated a lack of therapeutic benefit. Current research has focused on selecting a subpopulation of cancer patients who may benefit from TRAIL-based therapy and identifying best drugs to work with TRAIL. In the current study, we found that NSCLC cells with a KRAS mutation were highly sensitive to treatment with TRAIL and 5-fluorouracil (5FU). Compared with other chemotherapeutic agents, 5FU displayed the highest synergy with TRAIL in inducing apoptosis in mutant KRAS NSCLC cells. We also found that, on a mechanistic level, 5FU preferentially repressed survivin expression and induced expression of TRAIL death receptor 5 to sensitize NSCLC cells to TRAIL. The combination of low-dose 5FU and TRAIL strongly inhibited xenograft tumor growth in mice. Our results suggest that the combination of TRAIL and 5FU may be beneficial for patients with mutant KRAS NSCLC.

Macropinocytosis Exploitation by Cancers and Cancer Therapeutics

“…Cancers down-regulate cell-surface death receptors (DRs) via macropinocytosis in an H-Ras dependent manner to evade TNF-related apoptosis-inducing ligands (TRAILs) and subsequent apoptosis (Chen et al, 2014 ). Interestingly, certain cancers with either K- or H-Ras mutations can still be sensitive to TRAILs as other receptors and downstream signaling components may affect DR internalization via macropinocytosis (Drosopoulos et al, 2005 ; Wang et al, 2015 ). Interestingly, cancers can utilize macropinocytosis to internalize and activate receptors.…”

IAP antagonists Birinapant and AT-406 efficiently synergise with either TRAIL, BRAF, or BCL-2 inhibitors to sensitise BRAFV600E colorectal tumour cells to apoptosis

“…Moreover, many studies have shown that TRAIL is more efficient in induction of cancer cell death in combined treatments [ 22 ]. In recent studies, 5-Fluorouracil displayed synergy with TRAIL in inducing apoptosis in mutant KRAS non-small cell lung carcinoma cells [ 23 ]; TRAIL-R2-specific antibodies and recombinant TRAIL can synergise to kill cancer cells [ 24 ].…”

Effects of Recombinant Circularly Permuted Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) (Recombinant Mutant Human TRAIL) in Combination with 5-Fluorouracil in Human Colorectal Cancer Cell Lines HCT116 and SW480

“…5-fluorouracil (5-FU) is the first-line drug used for the treatment of CRC. Furthermore, a series of studies has shown that 5FU could promote TRAIL-induced apoptosis of a variety of cancer cell lines in vitro and in vivo [ 30 – 34 ].…”