ArticleOncotarget2017
Concomitant inhibition of receptor tyrosine kinases and downstream AKT synergistically inhibited growth of KRAS/BRAF mutant colorectal cancer cells.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
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- Capturing dynamic relevance in Boolean networks using graph theoretical measures.Bioinformatics (Oxford, England) · 2021Article
- Anticancer Activity of Triazolo-Thiadiazole Derivatives and Inhibition of AKT1 and AKT2 Activation.Pharmaceutics · 2021Article
- Therapeutic Suppression of FAK-AKT Signaling Overcomes Resistance to SHP2 Inhibition in Colorectal Carcinoma.Frontiers in pharmacology · 2021Article
- Concepts in Boolean network modeling: What do they all mean?Computational and structural biotechnology journal · 2020Review
- Article
- Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines.Journal of experimental & clinical cancer research : CR · 2019Article
- Targeting AKT/PKB to improve treatment outcomes for solid tumors.Mutation researchReview
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Receptor tyrosine kinase (RTK) signaling pathways are frequently activated in cancer cells due to mutations of RTKs and/or their downstream signaling proteins such as KRAS and BRAF. About 40% colorectal cancers (CRCs) contain KRAS or BRAF mutant genes and are resistant to treatments with individual inhibitors of RTKs, AKT, MEK, or BRAF. Therefore, an understanding of the molecular mechanisms of the drug resistance is necessary for developing effective strategies to treat the diseases. Here we report the discovery of an AKT/ERK reactivation mechanism that account for the cancer cell resistance to the AKT and MEK inhibitors treatments. The reactivations of AKT and ERK after the AKT or MEK inhibitor treatment were caused by a relief of an AKT or ERK-mediated feedback inhibition of the RTKs and/or their downstream pathways. A combination of RTK inhibitors, based on the RTK activation/phosphorylation profile, synergized with the AKT inhibitor, but not the MEK inhibitor, to completely inhibit the AKT phosphorylation and to block the growth of KRAS/BRAF mutant CRC cells. These results underscored the importance of AKT and the AKT feedback signaling to cancer cell growth and offered a novel therapeutic approach for the treatment of KRAS/BRAF mutant CRC cells.
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