Laroche Audrey, Tran-Cong Kevin, Chaire Vanessa, Lagarde Pauline, Hostein Isabelle, Coindre Jean-Michel, Chibon Frederic, Neuville Agnes, Lesluyes Tom, Lucchesi Carlo, Italiano Antoine
INSERM U916, Institut Bergonié, Bordeaux, France; Sarcoma Unit, Institut Bergonié, Bordeaux, France.
Pathology Department, Institut Bergonié, Bordeaux, France.
PLoS One. 2015 Oct 1;10(10):e0137794. doi: 10.1371/journal.pone.0137794. eCollection 2015.
Nutlin inhibits TP53-MDM2 interaction and is under investigation in soft-tissue sarcomas (STS) and other malignancies. Molecular mechanisms of secondary resistance to nutlin in STS are unknown. We performed whole-transcriptome sequencing (RNA-seq) on three pretreatment and secondary resistant STS cell lines selected based on their high primary sensitivity to nutlin. Our data identified a subset of cancer gene mutations and ploidy variations that were positively selected following treatment, including TP53 mutations in 2 out of 3 resistant cell lines. Further, secondary resistance to nutlin was associated with deregulation of apoptosis-related genes and marked productive autophagy, the inhibition of which resulted in significant restoration of nutlin-induced cell death. Collectively, our findings argue that secondary resistance to nutlin in STS involved heterogeneous mechanisms resulting from clonal evolution and several biological pathways. Alternative dosing regimens and combination with other targeted agents are needed to achieve successful development of nutlin in the clinical setting.
Nutlin可抑制TP53与MDM2的相互作用，目前正在软组织肉瘤（STS）和其他恶性肿瘤中进行研究。STS对Nutlin产生继发性耐药的分子机制尚不清楚。我们对三种基于对Nutlin的高初始敏感性而选择的预处理和继发性耐药STS细胞系进行了全转录组测序（RNA-seq）。我们的数据确定了一组在治疗后被正向选择的癌症基因突变和倍性变异，包括3个耐药细胞系中的2个出现TP53突变。此外，对Nutlin的继发性耐药与凋亡相关基因的失调和显著的有效自噬有关，抑制自噬可导致Nutlin诱导的细胞死亡显著恢复。总体而言，我们的研究结果表明，STS对Nutlin的继发性耐药涉及克隆进化和多种生物学途径导致的异质性机制。需要采用替代给药方案并与其他靶向药物联合使用，才能在临床环境中成功开发Nutlin。
