title: Failure to induce apoptosis via BCL-2 family proteins underlies lack of efficacy of combined MEK and PI3K inhibitors for KRAS-mutant lung cancers.
abstract: Although several groups have demonstrated that concomitant use of MEK and phosphoinositide 3-kinase (PI3K) inhibitors (MEKi/PI3Ki) can induce dramatic tumor regressions in mouse models of KRAS-mutant non-small cell lung cancer (NSCLC), ongoing clinical trials investigating this strategy have been underwhelming to date. While efficacy may be hampered by a narrow therapeutic index, the contribution of biologic heterogeneity in the response of KRAS-mutant NSCLCs to MEKi/PI3Ki has been largely unexplored. In this study, we find that most human KRAS-mutant NSCLC cell lines fail to undergo marked apoptosis in response to MEKi/PI3Ki, which is key for tumor responsiveness in vivo. This heterogeneity of apoptotic response occurs despite relatively uniform induction of growth arrest. Using a targeted short hairpin RNA screen of BCL-2 family members, we identify BIM, PUMA, and BCL-XL as key regulators of the apoptotic response induced by MEKi/PI3Ki, with decreased expression of BIM and PUMA relative to BCL-XL in cell lines with intrinsic resistance. In addition, by modeling adaptive resistance to MEKi/PI3Ki both in vitro and in vivo, we find that, upon the development of resistance, tumors have a diminished apoptotic response due to downregulation of BIM and PUMA. These results suggest that the inability to induce apoptosis may limit the effectiveness of MEKi/PI3Ki for KRAS-mutant NSCLCs by contributing to intrinsic and adaptive resistance to this therapy.
authors.affiliation: Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, MassachusettsAuthors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Hata
authors.affiliation: Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Alan
authors.initials: A
authors.lastname: Yeo
authors.affiliation: Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Faber
authors.affiliation: Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Eugene
authors.initials: E
authors.lastname: Lifshits
authors.affiliation: Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, MassachusettsAuthors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Cheng
authors.affiliation: Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Zandra
authors.initials: Z
authors.lastname: Walton
authors.affiliation: Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Kristopher A
authors.initials: KA
authors.lastname: Sarosiek
authors.affiliation: Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.affiliation: Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, MassachusettsAuthors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Heist
authors.affiliation: Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.affiliation: Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, MassachusettsAuthors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Authors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, MassachusettsAuthors' Affiliations: Massachusetts General Hospital Cancer Center, Charlestown; Department of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts jengelman@partners.org.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D018631:ras Proteins