Combination therapy targeting BCL6 and phospho-STAT3 defeats intratumor heterogeneity in a subset of non-small cell lung cancers

Dhruba Deb, Satwik Rajaram, Jill E. Larsen, Patrick D. Dospoy, Rossella Marullo, Long Shan Li, Kimberley Avila, Fengtian Xue, Leandro Cerchietti, John D. Minna, Steven J. Altschuler, Lani F. Wu

Research output: Contribution to journalArticle

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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 of TP53, KRAS, and MYC - 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 identified BCL6, 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.

Original languageEnglish (US)
Pages (from-to)3070-3081
Number of pages12
JournalCancer Research
Volume77
Issue number11
DOIs
StatePublished - Jun 1 2017

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Non-Small Cell Lung Carcinoma
Oncogenes
Down-Regulation
Neoplasms
MAP Kinase Signaling System
Therapeutics
Computational Biology
Lung Neoplasms
Up-Regulation
Epithelial Cells
Cell Line
Growth
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Combination therapy targeting BCL6 and phospho-STAT3 defeats intratumor heterogeneity in a subset of non-small cell lung cancers. / Deb, Dhruba; Rajaram, Satwik; Larsen, Jill E.; Dospoy, Patrick D.; Marullo, Rossella; Li, Long Shan; Avila, Kimberley; Xue, Fengtian; Cerchietti, Leandro; Minna, John D.; Altschuler, Steven J.; Wu, Lani F.

In: Cancer Research, Vol. 77, No. 11, 01.06.2017, p. 3070-3081.

Research output: Contribution to journalArticle

Deb, Dhruba ; Rajaram, Satwik ; Larsen, Jill E. ; Dospoy, Patrick D. ; Marullo, Rossella ; Li, Long Shan ; Avila, Kimberley ; Xue, Fengtian ; Cerchietti, Leandro ; Minna, John D. ; Altschuler, Steven J. ; Wu, Lani F. / Combination therapy targeting BCL6 and phospho-STAT3 defeats intratumor heterogeneity in a subset of non-small cell lung cancers. In: Cancer Research. 2017 ; Vol. 77, No. 11. pp. 3070-3081.
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AU - Larsen, Jill E.

AU - Dospoy, Patrick D.

AU - Marullo, Rossella

AU - Li, Long Shan

AU - Avila, Kimberley

AU - Xue, Fengtian

AU - Cerchietti, Leandro

AU - Minna, John D.

AU - Altschuler, Steven J.

AU - Wu, Lani F.

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AB - 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 of TP53, KRAS, and MYC - 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 identified BCL6, 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.

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