Activity of HSP90 Inhibiton in a Metastatic Lung Cancer Patient With a Germline BRCA1 Mutation. (26th February 2018)

• Record Type: Journal Article
• Authors: Cedrés, Susana; Felip, Enriqueta; Cruz, Cristina; Martinez de Castro, Ana; Pardo, Nuria; Navarro, Alejandro; Martinez-Marti, Alex; Remon, Jordin; Zeron-Medina, Jorge; Balmaña, Judith; Llop-Guevara, Alba; Miquel, Josep M; Sansano, Irene; Nuciforo, Paolo; Mancuso, Francesco; Serra, Violeta; Vivancos, Ana
• Is Part Of: Journal of the National Cancer Institute. Volume 110:Number 8(2018)
• Page Start: 914
• Page End: 917
• Publication Date: 2018-02-26
• Subjects: Cancer -- Periodicals; Cancer -- Research -- Periodicals; 616.994
• DOI: 10.1093/jnci/djy012
• Languages: English
• ISSNs: 0027-8874

Abstract

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.