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Plasticity of Extrachromosomal and Intrachromosomal BRAF Amplifications in Overcoming Targeted Therapy Dosage Challenges.
Song, Kai; Minami, Jenna K; Huang, Arthur; Dehkordi, Siavash R; Lomeli, Shirley H; Luebeck, Jens; Goodman, Mark H; Moriceau, Gatien; Krijgsman, Oscar; Dharanipragada, Prashanthi; Ridgley, Trevor; Crosson, William P; Salazar, Jesus; Pazol, Eli; Karin, Gabriel; Jayaraman, Rachana; Balanis, Nikolas G; Alhani, Salwan; Sheu, Kyle; Ten Hoeve, Johanna; Palermo, Amelia; Motika, Stephen E; Senaratne, T Niroshi; Paraiso, Kim H; Hergenrother, Paul J; Rao, P Nagesh; Multani, Asha S; Peeper, Daniel S; Bafna, Vineet; Lo, Roger S; Graeber, Thomas G.
Afiliación
  • Song K; Department of Bioengineering, University of California, Los Angeles, California.
  • Minami JK; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Huang A; Department of Integrative Biology and Physiology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Dehkordi SR; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Lomeli SH; Department of Computer Science and Engineering, University of California, San Diego, La Jolla, California.
  • Luebeck J; Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Goodman MH; Department of Computer Science and Engineering, University of California, San Diego, La Jolla, California.
  • Moriceau G; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Krijgsman O; Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Dharanipragada P; Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Ridgley T; Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Crosson WP; Bioinformatics Interdepartmental Program, University of California, Los Angeles, California.
  • Salazar J; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Pazol E; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Karin G; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Jayaraman R; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Balanis NG; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Alhani S; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Sheu K; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Ten Hoeve J; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Palermo A; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Motika SE; University of California, Los Angeles, Metabolomics Center, Los Angeles, California.
  • Senaratne TN; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Paraiso KH; University of California, Los Angeles, Metabolomics Center, Los Angeles, California.
  • Hergenrother PJ; Department of Chemistry, Institute for Genomic Biology, Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Illinois.
  • Rao PN; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Multani AS; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Peeper DS; Department of Chemistry, Institute for Genomic Biology, Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Illinois.
  • Bafna V; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
  • Lo RS; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Graeber TG; Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Cancer Discov ; 12(4): 1046-1069, 2022 04 01.
Article en En | MEDLINE | ID: mdl-34930786
ABSTRACT
Focal amplifications (FA) can mediate targeted therapy resistance in cancer. Understanding the structure and dynamics of FAs is critical for designing treatments that overcome plasticity-mediated resistance. We developed a melanoma model of dual MAPK inhibitor (MAPKi) resistance that bears BRAFV600 amplifications through either extrachromosomal DNA (ecDNA)/double minutes (DM) or intrachromosomal homogenously staining regions (HSR). Cells harboring BRAFV600E FAs displayed mode switching between DMs and HSRs, from both de novo genetic changes and selection of preexisting subpopulations. Plasticity is not exclusive to ecDNAs, as cells harboring HSRs exhibit drug addiction-driven structural loss of BRAF amplicons upon dose reduction. FA mechanisms can couple with kinase domain duplications and alternative splicing to enhance resistance. Drug-responsive amplicon plasticity is observed in the clinic and can involve other MAPK pathway genes, such as RAF1 and NRAS. BRAF FA-mediated dual MAPKi-resistant cells are more sensitive to proferroptotic drugs, extending the spectrum of ferroptosis sensitivity in MAPKi resistance beyond cases of dedifferentiation.

SIGNIFICANCE:

Understanding the structure and dynamics of oncogene amplifications is critical for overcoming tumor relapse. BRAF amplifications are highly plastic under MAPKi dosage challenges in melanoma, through involvement of de novo genomic alterations, even in the HSR mode. Moreover, BRAF FA-driven, dual MAPKi-resistant cells extend the spectrum of resistance-linked ferroptosis sensitivity. This article is highlighted in the In This Issue feature, p. 873.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas B-raf / Melanoma Límite: Humans Idioma: En Revista: Cancer Discov Año: 2022 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas B-raf / Melanoma Límite: Humans Idioma: En Revista: Cancer Discov Año: 2022 Tipo del documento: Article