Identification of a RAS-activating TMEM87A-RASGRF1 Fusion in an Exceptional Responder to Sunitinib with Non-Small Cell Lung Cancer.

Autor:	Cooper AJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., Kobayashi Y; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Kim D; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Clifford SE; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Kravets S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Dahlberg SE; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Chambers ES; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Li J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Rangachari D; Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center (a member of Beth Israel Lahey Health), Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Nguyen T; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Costa DB; Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center (a member of Beth Israel Lahey Health), Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Rabin MS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Wagle N; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Sholl LM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Jänne PA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Oxnard GR; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. geoffrey_oxnard@dfci.harvard.edu.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Aug 01; Vol. 26 (15), pp. 4072-4079. Date of Electronic Publication: 2020 Apr 20.
DOI:	10.1158/1078-0432.CCR-20-0397
Abstrakt:	Purpose: We pursued genomic analysis of an exceptional responder with non-small cell lung cancer (NSCLC) through a multi-platform effort to discover novel oncogenic targets. Experimental Design: In this open-label, single-arm phase II study (NCT01829217), an enriched cohort of patients with advanced NSCLC was treated with the multi-kinase inhibitor sunitinib. The primary endpoint was objective response rate. Tissue was collected for multi-platform genomic analysis of responders, and a candidate oncogene was validated using in vitro models edited by CRISPR-Cas9. Results: Of 13 patients enrolled, 1 patient (8%), a never smoker, had a partial response lasting 33 months. Genomic analysis of the responder identified no oncogenic variant using multi-platform DNA analysis including hotspot allelotyping, massively parallel hybrid-capture next-generation sequencing, and whole-exome sequencing. However, bulk RNA-sequencing (RNA-seq) revealed a novel fusion, TMEM87A-RASGRF1 , with high overexpression of the fusion partners. RASGRF1 encodes a guanine exchange factor which activates RAS from GDP-RAS to GTP-RAS. Oncogenicity was demonstrated in NIH/3T3 models with intrinsic TMEM87A-RASGRF1 fusion. In addition, activation of MAPK was shown in PC9 models edited to express this fusion, although sensitivity to MAPK inhibition was seen without apparent sensitivity to sunitinib. Conclusions: Sunitinib exhibited limited activity in this enriched cohort of patients with advanced NSCLC. Nonetheless, we find that RNA-seq of exceptional responders represents a potentially underutilized opportunity to identify novel oncogenic targets including oncogenic activation of RASGRF1. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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