The DNA damage response pathway as a land of therapeutic opportunities for colorectal cancer

被引:66
作者
Mauri, G. [1 ,2 ]
Arena, S. [3 ,4 ]
Siena, S. [1 ,2 ]
Bardelli, A. [3 ,4 ]
Sartore-Bianchi, A. [1 ,2 ]
机构
[1] Grande Osped Metropolitano Niguarda, Niguarda Canc Ctr, Milan, Italy
[2] Univ Milan, Dept Oncol & Hematooncol, Milan, Italy
[3] FPO IRCCS, Candiolo Canc Inst, Candiolo, TO, Italy
[4] Univ Torino, Dept Oncol, Candiolo, TO, Italy
关键词
DNA damage response; PARP inhibitors; PARPness; BRCA; ATM; colorectal cancer; HOMOLOGOUS RECOMBINATION DEFICIENCY; CONSENSUS MOLECULAR SUBTYPES; PARP INHIBITOR ABT-888; PHASE-I; MICROSATELLITE INSTABILITY; MUTATIONAL SIGNATURES; OVARIAN-CARCINOMA; REPAIR DEFECTS; CELLS; PLATINUM;
D O I
10.1016/j.annonc.2020.05.027
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Colorectal cancer (CRC) represents a major cause of cancer deaths worldwide. Although significant progress has been made by molecular and immune therapeutic approaches, prognosis of advanced stage disease is still dismal. Alterations in the DNA damage response (DDR) pathways are emerging as novel targets for treatment across different cancer types. However, even though preclinical studies have shown the potential exploitation of DDR alterations in CRC, systematic and comprehensive testing is lagging and clinical development is based on analogies with other solid tumors according to a tissue-agnostic paradigm. Recently, functional evidence from patient-derived xenografts and organoids have suggested that maintenance with PARP inhibitors might represent a therapeutic opportunity in CRC patients previously responsive to platinum-based treatment. Design and Result: In this review, we highlight the most promising preclinical data and systematically summarize published clinical trials in which DDR inhibitors have been used for CRC and provide evidence that disappointing results have been mainly due to a lack of clinical and molecular selection. Conclusions: Future preclinical and translational research will help in better understanding the role of DDR alterations in CRC and pave the way to novel strategies that might have a transformative impact on treatment by identifying new therapeutic options including tailored use of standard chemotherapy.
引用
收藏
页码:1135 / 1147
页数:13
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