Multi-omic and functional screening reveal targetable vulnerabilities in TP53 mutated multiple myeloma

Dimitrios Tsallos, Nemo K. Ikonen, Juho J. Miettinen, Muntasir M. Majumder, Samuli Eldfors, Imre Västrik, Alun Parsons, Minna Suvela, Katie Dunphy, Paul Dowling, Despina Bazou, Peter O'Gorman, Juha Lievonen, Raija Silvennoinen, Pekka Anttila, Caroline A. Heckman
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Abstract

Despite development of several effective therapies for multiple myeloma (MM), the prognosis of patients with partial deletion of chromosome 17 (del(17p)) and TP53 aberrations remains poor. By applying comprehensive multi-omics profiling analyses (whole exome and transcriptome sequencing plus proteomics) and functional ex vivo drug screening to samples from 167 patients with MM, we uncovered novel therapeutic vulnerabilities specific to TP53 mutated MM. Our findings revealed a distinct sensitivity profile to a range of inhibitors (mitotic, topoisomerase, HDAC, HSP90, IGF1R and PI3K/AKT/mTOR inhibitors) irrespective of 17p deletion status. Conversely, no increase in sensitivity was observed for monoallelic TP53 (del(17p) with WT TP53) when compared to WT TP53 samples, highlighting the remaining unmet clinical need. Notably, plicamycin, an RNA synthesis inhibitor linked to modulation of chromatin structure and increased transcription, emerged as particularly efficacious for TP53 mutated MM. The increased sensitivity correlated with higher protein expression of the drug targets: HDAC2, HSP90AA1 and multiple ribosomal subunits. Additionally, we observed increased RNA expression of G2M checkpoint, E2F targets and mTORC1 signaling in our cohort and the MMRF-CoMMpass (NCT01454297) study in TP53 mutated MM. Harmonization of multi-omics data with ex vivo drug screening results revealed that TP53 mutated MM is functionally distinct from MM with monoallelic TP53, and demonstrate that MM with mutated TP53, with and without del(17p), may be targetable by approved drugs, and further indicates the need for regular monitoring by sequencing to identify these patients.
多组学和功能筛选揭示 TP53 突变多发性骨髓瘤中的可靶向漏洞
尽管针对多发性骨髓瘤(MM)开发出了多种有效疗法,但17号染色体部分缺失(del(17p))和TP53畸变患者的预后仍然很差。通过对167名多发性骨髓瘤患者的样本进行全面的多组学分析(全外显子组和转录组测序加蛋白质组学)和功能性体外药物筛选,我们发现了TP53突变多发性骨髓瘤特有的新型治疗弱点。我们的研究结果表明,无论17p缺失状态如何,患者对一系列抑制剂(有丝分裂抑制剂、拓扑异构酶抑制剂、HDAC抑制剂、HSP90抑制剂、IGF1R抑制剂和PI3K/AKT/mTOR抑制剂)的敏感性各不相同。相反,与 WT TP53 样本相比,单倍性 TP53(del(17p) 与 WT TP53)的敏感性未见提高,这说明临床需求仍未得到满足。值得注意的是,与染色质结构调整和转录增加有关的 RNA 合成抑制剂普利霉素对 TP53 突变的 MM 尤为有效。敏感性的提高与药物靶点蛋白表达量的增加有关:HDAC2、HSP90AA1 和多个核糖体亚基的蛋白表达量增加。此外,在我们的队列和 MMRF-CoMMpass (NCT01454297) 研究中,我们观察到 TP53 突变 MM 中 G2M 检查点、E2F 靶点和 mTORC1 信号转导的 RNA 表达增加。多组学数据与体内外药物筛选结果的统一显示,TP53突变的MM在功能上有别于TP53单拷贝的MM,并证明TP53突变的MM,无论有无del(17p),都有可能成为已批准药物的靶点,并进一步表明有必要通过测序进行定期监测,以识别这些患者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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