Activity of HSP90 Inhibiton in a Metastatic Lung Cancer Patient With a Germline BRCA1 Mutation
Cedrés, Susana (Hospital Universitari Vall d'Hebron)
Felip, Enriqueta (Universitat Autònoma de Barcelona)
Cruz Zambrano, Cristina (Hospital Universitari Vall d'Hebron)
Martinez de Castro, Ana (Hospital Universitari Vall d'Hebron)
Pardo Aranda, Nuria (Universitat Autònoma de Barcelona)
Navarro, Alejandro (Universitat Autònoma de Barcelona)
Martinez-Marti, Alex (Universitat Autònoma de Barcelona)
Remon, Jordin (Vall d'Hebron Institut d'Oncologia)
Zeron-Medina, Jorge (Hospital Universitari Vall d'Hebron)
Balmaña Gelpí, Judith (Universitat Autònoma de Barcelona)
Llop-Guevara, Alba (Vall d'Hebron Institut d'Oncologia)
Miquel, Josep M. (Vall d'Hebron Institut d'Oncologia)
Sansano, Irene (Pathology Department)
Nuciforo, Paolo (Molecular Oncology Group)
Mancuso, Francesco M (Cancer Genomic Group)
Serra, Violeta (Experimental Therapeutic Group)
Vivancos, Ana (Cancer Genomic Group)

Date:	2018
Abstract:	Heat shock proteins (HSPs) are molecular chaperones that maintain proteins in their correct conformation to ensure stability and protect carcinoma cells from apoptosis. HSP90 inhibitors (HSP90i) block multiple targets simultaneously, and despite responses in a selected population, no HSP90i have yet been approved. We present a patient with a lung tumor with an exceptional response to cisplatin/gemcitabine in combination with HSP90i, which nowadays continues with HSP90i maintenance after three years. Whole-exome sequencing of the lung tumor unveiled a BRCA1/2 deficiency mutational signature, and mutation analysis confirmed a germline BRCA1 mutation. The striking efficacy of HSP90i plus chemotherapy vs chemotherapy alone was reproduced in a patient-derived xenograft (PDX) model from a breast cancer patient with a BRCA1 mutation (mean tumor volume [SD], No. of tumors: vehicle 8. 38 [7. 07] mm 3, n = 3; HSP90i 4. 18 [1. 93] mm 3, n = 5; cisplatin plus gemcitabine 3. 31 [1. 95] mm 3, n = 5; cisplatin plus gemcitabine plus HSP90i 0. 065 [0. 076] mm 3, n = 6). This case and the PDX demonstrate the efficacy for therapeutic inhibition of HSP90 in a BRCA- mutated patient, opening a new potential avenue for better identifying patients who might benefit most from HSP90i.
Grants:	Instituto de Salud Carlos III PI17-01080 Instituto de Salud Carlos III CP14-00228 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014 SGR 133
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Journal of the National Cancer Institute, Vol. 110 (february 2018) , p. 914-917, ISSN 1460-2105

DOI: 10.1093/jnci/djy012
PMID: 29529211

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