Cancer Cell`s Seven Achilles Heels: Consideration for desing of anti-cancer drug combinations.
Gahramanov, V.; Vizeacoumar, F. S.; Morales, A. M.; Bonham, K.; Sakharkar, M. K.; Vizeacoumar, F. J.; Freywald, A.; Sherman, M. Y. Y.
Show abstract
Loss of function screens using shRNA and CRISPR are routinely used to identify genes that modulate responses of tumor cells to anti-cancer drugs. Here, by integrating GSEA and CMAP analyses of multiple published shRNA screens, we identified a core set of pathways that affect responses to multiple drugs with diverse mechanisms of action. This suggests that these pathways represent "weak points" or "Achilles heels", whose mild disturbance should make cancer cells vulnerable to a variety of treatments. These "weak points" include proteasome, protein synthesis, RNA splicing, RNA synthesis, cell cycle, Akt-mTOR, and tight junction-related pathways. Therefore, inhibitors of these pathways are expected to sensitize cancer cells to a variety of drugs. This hypothesis was tested by analyzing the diversity of drugs that synergize with FDA-approved inhibitors of the proteasome, RNA synthesis, and Akt-mTOR pathways. Indeed, the quantitative evaluation indicates that inhibitors of any of these signaling pathways can synergize with a more diverse set of pharmaceuticals, compared to compounds inhibiting targets distinct from the "weak points" pathways. Our findings described here imply that inhibitors of the "weak points" pathways should be considered as primary candidates in a search for synergistic drug combinations.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Exploring NCATS In-House Biomedical Data for Evidence-based Drug Repurposing 94%
- P16 methylation increases the sensitivity of cancer cells to the CDK4/6 inhibitor palbociclib 94%
- A novel small molecule LLL12B inhibits STAT3 signaling and sensitizes ovarian cancer cell to paclitaxel and cisplatin 94%
Similar papers in this journal
- Multiscale Analysis And Validation Of Effective Drug Combinations Targeting Driver Kras Mutations In Non-Small Cell Lung Cancer 96%
- A small molecule that promotes cellular senescence prevents fibrogenesis and tumorigenesis in vitro 93%
- DReAmocracy: A Method to Capitalize on Prior Drug Discovery Efforts to Highlight Candidate Drugs for Repurposing 93%
Similar papers in this journal
- Tegaserod maleate suppresses the growth of gastric cancer in vivo and in vitro by targeting MEK1/2 93%
- Synthetic lethality screening identifies FDA-approved drugs that overcome ATP7B-mediated tolerance of tumor cells to cisplatin 93%
- Drug-adapted cancer cell lines reveal drug-induced heterogeneity and enable the identification of biomarker candidates for the acquired resistance setting 92%
Similar papers in this journal
- Osthole Suppresses Prostate Cancer Progression by Modulating PRLR and the JAK2/STAT3 Signaling Axis 94%
- BNIP3 upregulation characterizes cancer cell subpopulation with increased fitness and proliferation 93%
- Patient stratification of clear cell renal cell carcinoma using the global transcription factor activity landscape derived from RNA-seq data 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.