title: Dynamic variations in epithelial-to-mesenchymal transition (EMT), ATM, and SLFN11 govern response to PARP inhibitors and cisplatin in small cell lung cancer.
abstract: Small cell lung cancer (SCLC) is one of the most aggressive forms of cancer, with a 5-year survival <7%. A major barrier to progress is the absence of predictive biomarkers for chemotherapy and novel targeted agents such as PARP inhibitors. Using a high-throughput, integrated proteomic, transcriptomic, and genomic analysis of SCLC patient-derived xenografts (PDXs) and profiled cell lines, we identified biomarkers of drug sensitivity and determined their prevalence in patient tumors. In contrast to breast and ovarian cancer, PARP inhibitor response was not associated with mutations in homologous recombination (HR) genes (e.g., BRCA1/2) or HRD scores. Instead, we found several proteomic markers that predicted PDX response, including high levels of SLFN11 and E-cadherin and low ATM. SLFN11 and E-cadherin were also significantly associated with in vitro sensitivity to cisplatin and topoisomerase1/2 inhibitors (all commonly used in SCLC). Treatment with cisplatin or PARP inhibitors downregulated SLFN11 and E-cadherin, possibly explaining the rapid development of therapeutic resistance in SCLC. Supporting their functional role, silencing SLFN11 reduced in vitro sensitivity and drug-induced DNA damage; whereas ATM knockdown or pharmacologic inhibition enhanced sensitivity. Notably, SCLC with mesenchymal phenotypes (i.e., loss of E-cadherin and high epithelial-to-mesenchymal transition (EMT) signature scores) displayed striking alterations in expression of miR200 family and key SCLC genes (e.g., NEUROD1, ASCL1, ALDH1A1, MYCL1). Thus, SLFN11, EMT, and ATM mediate therapeutic response in SCLC and warrant further clinical investigation as predictive biomarkers.
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: C
authors.initials: C
authors.lastname: Allison Stewart
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Pan
authors.initials: P
authors.lastname: Tong
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cardnell
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Triparna
authors.initials: T
authors.lastname: Sen
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lerong
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Carl M
authors.initials: CM
authors.lastname: Gay
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Fatemah
authors.initials: F
authors.lastname: Masrorpour
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: You
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Rasha O
authors.initials: RO
authors.lastname: Bara
authors.affiliation: BioMarin Pharmaceutical, San Rafael, CA 94901, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.affiliation: BioMarin Pharmaceutical, San Rafael, CA 94901, USA.
authors.forename: Yuanbin
authors.initials: Y
authors.lastname: Ru
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Junya
authors.initials: J
authors.lastname: Fujimoto
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Samrat T
authors.initials: ST
authors.lastname: Kundu
authors.affiliation: BioMarin Pharmaceutical, San Rafael, CA 94901, USA.
authors.forename: Leonard E
authors.initials: LE
authors.lastname: Post
authors.affiliation: BioMarin Pharmaceutical, San Rafael, CA 94901, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Yu
authors.affiliation: BioMarin Pharmaceutical, San Rafael, CA 94901, USA.
authors.forename: Yuqiao
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Bonnie S
authors.initials: BS
authors.lastname: Glisson
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Wistuba
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Don L
authors.initials: DL
authors.lastname: Gibbons
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lauren Averett
authors.initials: LA
authors.lastname: Byers
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D015415:Biomarkers; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
chemical_list: D015415:Biomarkers; D015820:Cadherins; D009687:Nuclear Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C576668:SLFN11 protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D002945:Cisplatin
keywords: ATM; EMT; PARP inhibitor; SCLC; SLFN11