Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer.
Anna-Lena ScherrAndreas MockGeorg GdyniaNathalie SchmittChristoph E HeiligFelix KorellPraveen RhadakrishnanPaula HoffmeisterKlaus H MetzelerHeike BantelAnna L IllertMelanie BoerriesJörg TrojanOliver WaidmannJohanna FalkenhorstJens SivekePhilipp J JostMichael BitzerNisar P MalekLoredana VecchioneIvan JelasBenedikt BrorsHanno GlimmAlbrecht StenzingerSvetlana P GrekovaTobias GehrigHenning Schulze-BergkamenDirk JägerPeter SchirmacherMathias HeikenwalderBenjamin GoeppertMartin SchneiderStefan FröhlingBruno C KöhlerPublished in: Cell death & disease (2020)
Since metastatic colorectal cancer (CRC) is a leading cause of cancer-related death, therapeutic approaches overcoming primary and acquired therapy resistance are an urgent medical need. In this study, the efficacy and toxicity of high-affinity inhibitors targeting antiapoptotic BCL-2 proteins (BCL-2, BCL-XL, and MCL-1) were evaluated. By RNA sequencing analysis of a pan-cancer cohort comprising >1500 patients and subsequent prediction of protein activity, BCL-XL was identified as the only antiapoptotic BCL-2 protein that is overactivated in CRC. Consistently, pharmacologic and genetic inhibition of BCL-XL induced apoptosis in human CRC cell lines. In a combined treatment approach, targeting BCL-XL augmented the efficacy of chemotherapy in vitro, in a murine CRC model, and in human ex vivo derived CRC tissue cultures. Collectively, these data show that targeting of BCL-XL is efficient and safe in preclinical CRC models, observations that pave the way for clinical translation.
Keyphrases
- induced apoptosis
- endothelial cells
- end stage renal disease
- healthcare
- oxidative stress
- metastatic colorectal cancer
- chronic kidney disease
- gene expression
- endoplasmic reticulum stress
- squamous cell carcinoma
- stem cells
- radiation therapy
- cancer therapy
- machine learning
- prognostic factors
- young adults
- mesenchymal stem cells
- big data
- drug delivery
- peritoneal dialysis
- cell therapy
- papillary thyroid
- copy number
- combination therapy
- small molecule
- deep learning
- amino acid
- genome wide
- squamous cell
- patient reported outcomes
- replacement therapy