ArticleMolecular cancer research : MCR2015
Reversal of Mutant KRAS-Mediated Apoptosis Resistance by Concurrent Noxa/Bik Induction and Bcl-2/Bcl-xL Antagonism in Colon Cancer Cells.
Article in Molecular cancer research : MCR, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- Challenges and opportunities in combining radiotherapy and immunotherapy for localized pancreatic cancer.Nature reviews. Gastroenterology & hepatology · 2026Review
- BCL-xL as a therapeutic target in cetuximab-refractory colorectal cancer.Cell death & disease · 2026Article
- Biological Clock Perspective in Rheumatoid Arthritis.Inflammation · 2025Review
- Crucial Role of OncogenicCells · 2022Review
- Differential expression analysis of genes and long non-coding RNAs associated with KRAS mutation in colorectal cancer cells.Scientific reports · 2022Article
- Expression of Parkin, APC, APE1, and Bcl-xL in Colorectal Polyps.The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2021Article
- BH3 Mimetic Sensitivity of Colorectal Cancer Cell Lines in Correlation with Molecular Features Identifies Predictors of Response.International journal of molecular sciences · 2021Article
- Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage.Cell communication and signaling : CCS · 2021Review
- Kras mutation subtypes distinctly affect colorectal cancer cell sensitivity to FL118, a novel inhibitor of survivin, Mcl-1, XIAP, cIAP2 and MdmX.American journal of translational research · 2021Article
- Immunogenic Cell Death: A Step Ahead of Autophagy in Cancer Therapy.Journal of cancer immunology · 2021Article
- Iatrogenic endometriosis harbors somatic cancer-driver mutations.Human reproduction (Oxford, England) · 2019Article
- The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Article
- Biphasic ROS production, p53 and BIK dictate the mode of cell death in response to DNA damage in colon cancer cells.PloS one · 2017Article
- Bcl-xL is an oncogenic driver in colorectal cancer.Cell death & disease · 2016Article
- Mechanisms of drug resistance in colon cancer and its therapeutic strategies.World journal of gastroenterology · 2016Review
- Review
- Article
- The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism.The Journal of biological chemistry · 2015Article
- Identification of potential glucocorticoid receptor therapeutic targets in multiple myeloma.Nuclear receptor signaling · 2015Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
unlabelledKRAS mutations are frequently detected in human colorectal cancer and contribute to de novo apoptosis resistance and ultimately therapeutic failure. To overcome KRAS-mediated apoptosis resistance, the irreversible proteasome inhibitor, carfilzomib, was evaluated and found to potently induce Noxa, which was dependent upon c-Myc, and Bik. Isogenic mutant versus wild-type KRAS carcinoma cells showed elevated Bcl-xL, confirmed by KRAS siRNA or ectopic expression. Upregulated Bcl-xL by mutant KRAS was mediated by ERK as indicated by ERK knockdown. Bcl-xL expression was regulated at the level of mRNA and protein as shown using actinomycin D and cyclohexamide, respectively. Suppression of Bcl-xL by shRNA sensitized mutant KRAS cells to carfilzomib. Concurrent Bcl-xL antagonism by the BH3 mimetic ABT-263 combined with carfilzomib synergistically enhanced apoptosis that was dependent on Bax or p53, and was attenuated by Noxa or Bik shRNA. In support of this strategy, ectopically expressed Noxa enhanced apoptosis by ABT-263. Carfilzomib-induced Noxa and Bik sequestered Mcl-1 and ABT-263 released Bik and Bak from Bcl-xL, suggesting a mechanism for drug synergy. These preclinical findings establish mutant KRAS-mediated Bcl-xL upregulation as a key mechanism of apoptosis resistance in KRAS-mutant colorectal cancer. Furthermore, antagonizing Bcl-xL enabled carfilzomib-induced Noxa and Bik to induce synergistic apoptosis that reversed KRAS-mediated resistance. IMPLICATIONS: This novel study reveals a promising treatment strategy to overcome apoptosis resistance in KRAS-mutant colorectal cancer by concurrent upregulation of Noxa/Bik and antagonism of Bcl-xL.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.