SCLC PDX Chemoresistance Cohort (Gardner 2017)

Overview

10 paired patient-derived xenograft (PDX) models of small cell lung cancer (SCLC) from Memorial Sloan Kettering Cancer Center and Johns Hopkins University. Each model was serially treated in vivo with cisplatin/etoposide to derive matched chemonaive and chemoresistant tumors. The cohort was used to characterize transcriptomic and epigenetic mechanisms of acquired chemoresistance, focusing on SLFN11 silencing via EZH2-mediated H3K27me3 deposition. Raw data deposited in dbGaP under accession phs001249.v1.p1.

Composition

  • 10 paired SCLC PDX models — chemonaive vs. acquired-chemoresistant; majority derived from chemonaive patients. Two models (MSK-LX40 and MSK-LX95) had matched normal DNA. Named models include JHU-LX102, SCRX-Lu149, JHU-LX44 (chemorefractory at baseline), and others.
  • Murine SCLC models — Rb1/Trp53-null (DKO) and Rb1/Rbl2/Trp53-null (TKO) cell lines; chemonaive allograft TKO-A and its chemoresistant derivative TKO-AR.
  • SCLC cell lines — NCI-H82, NCI-H446, NCI-H526 used for mechanistic experiments.
  • Clinical TMAs — untreated SCLC (Vanderbilt Medical Center) and previously-treated SCLC (Case Western Reserve University) for SLFN11 IHC validation.
  • Cancer types: SCLC.

Assays / panels (linked)

  • Whole-exome sequencing — paired chemonaive/resistant models; reads aligned to a custom human/mouse hybrid reference (GRCh38 + GRCm38.p3).
  • RNA-seq — paired chemonaive/resistant models.
  • ChIP-seq — EZH2, H3K27me3, and H3K27Ac in SCRX-Lu149 chemoresistant tumors.
  • ChIP-qPCR — SLFN11 gene-body H3K27me3 quantification.
  • Immunohistochemistry — SLFN11 IHC H-score on clinical TMAs.

Papers using this cohort

  • PMID:28196596 — Gardner et al. 2017, Cancer Cell: EZH2-mediated SLFN11 silencing drives acquired chemoresistance in SCLC PDX models; EZH2 inhibition (EPZ011989) restores chemosensitivity and synergizes with irinotecan in vivo.

Notable findings derived from this cohort

  • Whole-exome sequencing of 10 paired SCLC PDX models revealed no recurrent acquired somatic mutations driving chemoresistance; resistant models retained parental TP53 and RB1 driver alterations PMID:28196596.
  • RNA-seq identified two mutually exclusive transcriptional resistance programs across 7/10 chemoresistant models: SLFN11 downregulation (4/10 models) and TWIST1 upregulation with cancer-testis antigen induction (3/10 models) PMID:28196596.
  • ChIP-seq in SCRX-Lu149 demonstrated that EZH2 and H3K27me3 spread across the SLFN11 gene body in chemoresistant tumors, with concurrent loss of H3K27Ac at the TSS; EPZ011989 (EZH2 inhibitor) reversed this epigenetic silencing and re-expressed SLFN11 PMID:28196596.
  • TWIST1 induction accompanied EMT-like changes (E-cadherin loss) but functional experiments showed it is a biomarker rather than direct driver of acquired resistance PMID:28196596.
  • EPZ011989 combined with cisplatin/etoposide or irinotecan demonstrated potent combinatorial in vivo activity in SLFN11-high PDX models; single-agent EPZ had modest efficacy PMID:28196596.

Sources

  • dbGaP accession: phs001249.v1.p1
  • cBioPortal studyId: sclc_cancercell_gardner_2017
  • PMID:28196596

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