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PMID:23245996

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Citation

Corcoran, RB, Cheng, KA, Hata, AN, Faber, AC, Ebi, H, Coffee, EM, Greninger, P, Brown, RD, Godfrey, JT, Cohoon, TJ, Song, Y, Lifshits, E, Hung, KE, Shioda, T, Dias-Santagata, D, Singh, A, Settleman, J, Benes, CH, Mino-Kenudson, M, Wong, KK and Engelman, JA (2013) Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 23:121-8

Abstract

KRAS is the most commonly mutated oncogene, yet no effective targeted therapies exist for KRAS mutant cancers. We developed a pooled shRNA-drug screen strategy to identify genes that, when inhibited, cooperate with MEK inhibitors to effectively treat KRAS mutant cancer cells. The anti-apoptotic BH3 family gene BCL-XL emerged as a top hit through this approach. ABT-263 (navitoclax), a chemical inhibitor that blocks the ability of BCL-XL to bind and inhibit pro-apoptotic proteins, in combination with a MEK inhibitor led to dramatic apoptosis in many KRAS mutant cell lines from different tissue types. This combination caused marked in vivo tumor regressions in KRAS mutant xenografts and in a genetically engineered KRAS-driven lung cancer mouse model, supporting combined BCL-XL/MEK inhibition as a potential therapeutic approach for KRAS mutant cancers.

Links

PubMed PMC3667614 Online version:10.1016/j.ccr.2012.11.007

Keywords

Aniline Compounds/pharmacology; Aniline Compounds/therapeutic use; Animals; Antineoplastic Agents/pharmacology; Antineoplastic Agents/therapeutic use; Benzimidazoles/pharmacology; Benzimidazoles/therapeutic use; Drug Screening Assays, Antitumor; Humans; MAP Kinase Kinase Kinases/antagonists & inhibitors; Mice; Neoplasms/drug therapy; Neoplasms/genetics; Proto-Oncogene Proteins p21(ras)/genetics; Proto-Oncogene Proteins p21(ras)/metabolism; Sulfonamides/pharmacology; Sulfonamides/therapeutic use; bcl-X Protein/antagonists & inhibitors

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:B2L11

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q07817-1

F

Seeded From UniProt

complete

HUMAN:B2L11

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q07820

F

Seeded From UniProt

complete

HUMAN:B2CL1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O43521

F

Seeded From UniProt

complete

HUMAN:MCL1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O43521

F

Seeded From UniProt

complete

See also

References

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