Sarah Cannon Research Institute, Nashville, TN.
Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN.
Am Soc Clin Oncol Educ Book. 2022 Apr;42:1-13. doi: 10.1200/EDBK_351333.
Despite the discovery of oncogenes in human tumor DNA 40 years ago, the development of effective targeted therapies directed against has lagged behind those more successful advancements in the field of therapeutic tyrosine kinase inhibitors targeting other oncogenes such as , , and . The discoveries that (1) malignant oncogenes differ from their wild-type counterparts by only a single amino acid change and (2) covalent inhibition of the cysteine residue at codon 12 of in its inactive GDP-bound state resulted in effective inhibition of oncogenic RAS signaling and have catalyzed a dramatic shift in mindset toward -driven cancers. Although the development of allele-selective KRAS inhibitors has changed a treatment paradigm, the clinical activity of these agents is more modest than tyrosine kinase inhibitors targeting other oncogene-driven cancers. Heterogeneous resistance mechanisms generally result in the restoration of RAS/mitogen-activated protein kinase pathway signaling. Many approaches are being evaluated to overcome this resistance, with many combinatorial clinical trials ongoing. Furthermore, because and are more prevalent than , there remains an unmet need for additional therapeutic strategies for these patients. Thus, our current translational standing could be described as "the end of the beginning," with additional discovery and research innovation needed to address the enormous disease burden imposed by -mutant cancers. Here, we describe the development of KRAS inhibitors, the challenges of resistance to these inhibitors, strategies to mitigate that resistance, and new approaches being taken to address other -mutant cancers.
尽管 40 年前在人类肿瘤 DNA 中发现了致癌基因，但针对的有效靶向治疗的发展落后于针对其他致癌基因（如、和）的治疗性酪氨酸激酶抑制剂更成功的进展。这些发现：（1）恶性致癌基因与野生型相比仅发生单个氨基酸变化；（2）在其非活性 GDP 结合状态下，半胱氨酸残基的共价抑制导致有效的致癌 RAS 信号抑制，并促使思维发生重大转变，转向驱动的癌症。尽管等位基因选择性 KRAS 抑制剂的开发改变了治疗模式，但这些药物的临床活性比针对其他致癌基因驱动的癌症的酪氨酸激酶抑制剂更为温和。异质耐药机制通常导致 RAS/丝裂原活化蛋白激酶途径信号的恢复。正在评估许多方法来克服这种耐药性，许多组合临床试验正在进行中。此外，由于和比更为普遍，因此这些患者仍然需要额外的治疗策略。因此，我们目前的转化研究状况可以被描述为“开始的结束”，需要进一步的发现和研究创新来解决由突变癌症带来的巨大疾病负担。在这里，我们描述了 KRAS 抑制剂的开发、对这些抑制剂的耐药性的挑战、减轻这种耐药性的策略以及解决其他突变癌症的新方法。
