Research and Early Development Oncology, Pharmaceuticals, Bayer AG, Müllerstr. 178, 13353 Berlin, Germany.
Int J Mol Sci. 2024 Jan 5;25(2):705. doi: 10.3390/ijms25020705.
The advent of targeted therapies has led to tremendous improvements in treatment options and their outcomes in the field of oncology. Yet, many cancers outsmart precision drugs by developing on-target or off-target resistance mechanisms. Gaining the ability to resist treatment is the rule rather than the exception in tumors, and it remains a major healthcare challenge to achieve long-lasting remission in most cancer patients. Here, we discuss emerging strategies that take advantage of innovative high-throughput screening technologies to anticipate on- and off-target resistance mechanisms before they occur in treated cancer patients. We divide the methods into non-systematic approaches, such as random mutagenesis or long-term drug treatment, and systematic approaches, relying on the clustered regularly interspaced short palindromic repeats (CRISPR) system, saturated mutagenesis, or computational methods. All these new developments, especially genome-wide CRISPR-based screening platforms, have significantly accelerated the processes for identification of the mechanisms responsible for cancer drug resistance and opened up new avenues for future treatments.
靶向治疗的出现极大地改善了肿瘤学领域的治疗选择和疗效。然而，许多癌症通过形成靶内或靶外耐药机制来“智取”精准药物。在肿瘤中，获得抵抗治疗的能力是常态而非例外，对于大多数癌症患者实现持久缓解仍然是一个主要的医疗保健挑战。在这里，我们讨论了利用创新的高通量筛选技术的新兴策略，以便在接受治疗的癌症患者中出现靶内和靶外耐药机制之前预测它们。我们将这些方法分为非系统性方法，如随机诱变或长期药物治疗，以及系统性方法，依赖于成簇规律间隔短回文重复序列 (CRISPR) 系统、饱和诱变或计算方法。所有这些新的发展，特别是基于全基因组 CRISPR 的筛选平台，极大地加速了鉴定导致癌症药物耐药性的机制的过程，并为未来的治疗开辟了新途径。
