title: Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non-Small Cell Lung Cancers.
abstract: Oncogene-specific changes in cellular signaling have been widely observed in lung cancer. Here, we investigated how these alterations could affect signaling heterogeneity and suggest novel therapeutic strategies. We compared signaling changes across six human bronchial epithelial cell (HBEC) strains that were systematically transformed with various combinations ofTP53, KRAS, andMYC-oncogenic alterations commonly found in non-small cell lung cancer (NSCLC). We interrogated at single-cell resolution how these alterations could affect classic readouts (β-CATENIN, SMAD2/3, phospho-STAT3, P65, FOXO1, and phospho-ERK1/2) of key pathways commonly affected in NSCLC. All three oncogenic alterations were required concurrently to observe significant signaling changes, and significant heterogeneity arose in this condition. Unexpectedly, we found two mutually exclusive altered subpopulations: one with STAT3 upregulation and another with SMAD2/3 downregulation. Treatment with a STAT3 inhibitor eliminated the upregulated STAT3 subpopulation, but left a large surviving subpopulation with downregulated SMAD2/3. A bioinformatics search identifiedBCL6, a gene downstream of SMAD2/3, as a novel pharmacologically accessible target of our transformed HBECs. Combination treatment with STAT3 and BCL6 inhibitors across a panel of NSCLC cell lines and in xenografted tumors significantly reduced tumor cell growth. We conclude that BCL6 is a new therapeutic target in NSCLC and combination therapy that targets multiple vulnerabilities (STAT3 and BCL6) downstream of common oncogenes, and tumor suppressors may provide a potent way to defeat intratumor heterogeneity.Cancer Res; 77(11); 3070-81. ©2017 AACR.
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Dhruba
authors.initials: D
authors.lastname: Deb
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California.
authors.forename: Satwik
authors.initials: S
authors.lastname: Rajaram
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Larsen
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Dospoy
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, New York.
authors.forename: Rossella
authors.initials: R
authors.lastname: Marullo
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Long Shan
authors.initials: LS
authors.lastname: Li
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Avila
authors.affiliation: Departments of Pharmaceutical Sciences and Anesthesiology, University of Maryland, Baltimore, Maryland.
authors.forename: Fengtian
authors.initials: F
authors.lastname: Xue
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, New York.
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas. lani.wu@ucsf.edu Steven.Altschuler@ucsf.edu john.minna@utsouthwestern.edu.|Departments of Pharmacology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California. lani.wu@ucsf.edu Steven.Altschuler@ucsf.edu john.minna@utsouthwestern.edu.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Altschuler
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California. lani.wu@ucsf.edu Steven.Altschuler@ucsf.edu john.minna@utsouthwestern.edu.
authors.forename: Lani F
authors.initials: LF
authors.lastname: Wu
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: C084103:BCL6 protein, human; D051560:Proto-Oncogene Proteins c-bcl-6; D050796:STAT3 Transcription Factor