title: Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models.
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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Corcoran
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Cheng
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Hata
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Faber
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ebi
authors.forename: Erin M
authors.initials: EM
authors.lastname: Coffee
authors.forename: Patricia
authors.initials: P
authors.lastname: Greninger
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Brown
authors.forename: Jason T
authors.initials: JT
authors.lastname: Godfrey
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Cohoon
authors.forename: Youngchul
authors.initials: Y
authors.lastname: Song
authors.forename: Eugene
authors.initials: E
authors.lastname: Lifshits
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Hung
authors.forename: Toshi
authors.initials: T
authors.lastname: Shioda
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.forename: Anurag
authors.initials: A
authors.lastname: Singh
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: C517975:AZD 6244; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D013449:Sulfonamides; D051020:bcl-X Protein; D020930:MAP Kinase Kinase Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); C528561:navitoclax