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] mm³, n = 3; HSP90i 4.18 [1.93] mm³, n = 5; cisplatin plus gemcitabine 3.31 [1.95] mm³, n = 5; cisplatin plus gemcitabine plus HSP90i 0.065 [0.076] mm³, 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.

中文翻译：

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生殖细胞BRCA1突变的转移性肺癌患者中HSP90抑制剂的活性。

热休克蛋白（HSP）是分子伴侣，可将蛋白维持在正确的构象中，以确保稳定性并保护癌细胞免于凋亡。HSP90i抑制剂（HSP90i）同时阻断多个靶标，尽管在选定的人群中有反应，但尚未批准HSP90i。我们介绍了一位肺癌患者，对HSP90i联合使用顺铂/吉西他滨有特殊的反应，如今，这种情况在三年后仍继续对HSP90i进行维护。肺肿瘤的全外显子测序揭示了BRCA1 / 2缺乏突变特征，并且突变分析证实了生殖系BRCA1突变。在患有BRCA1突变的乳腺癌患者（平均肿瘤体积[SD]，肿瘤数量：媒介物8.38 [7.07] mm ³，n ＝ 3； HSP90i 4.18 [1.93] mm ³，n ＝ 5；顺铂加吉西他滨3.31 [1.95] mm ³，n ＝ 5；顺铂加吉西他滨加HSP90i 0.065 [0.076] mm ³，n ＝ 6）。该案例和PDX证明了对BRCA突变患者具有治疗抑制HSP90的功效，为更好地识别可能从HSP90i中受益最大的患者开辟了一条新的潜在途径。