Clinical Research Development and Phase I Unit, CREA Laboratory, ASST Spedali Civili di Brescia, Brescia, Italy.
Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Blood. 2021 Nov 4;138(18):1705-1720. doi: 10.1182/blood.2020010572.
Alterations in KRAS have been identified as the most recurring somatic variants in the multiple myeloma (MM) mutational landscape. Combining DNA and RNA sequencing, we studied 756 patients and observed KRAS as the most frequently mutated gene in patients at diagnosis; in addition, we demonstrated the persistence or de novo occurrence of the KRAS aberration at disease relapse. Small-molecule inhibitors targeting KRAS have been developed; however, they are selective for tumors carrying the KRASG12C mutation. Therefore, there is still a need to develop novel therapeutic approaches to target the KRAS mutational events found in other tumor types, including MM. We used AZD4785, a potent and selective antisense oligonucleotide that selectively targets and downregulates all KRAS isoforms, as a tool to dissect the functional sequelae secondary to KRAS silencing in MM within the context of the bone marrow niche and demonstrated its ability to significantly silence KRAS, leading to inhibition of MM tumor growth, both in vitro and in vivo, and confirming KRAS as a driver and therapeutic target in MM.
KRAS 中的改变已被确定为多发性骨髓瘤（MM）突变景观中最常见的体细胞变异。通过对 756 名患者进行 DNA 和 RNA 测序研究，我们观察到 KRAS 是诊断时基因突变最常见的基因；此外，我们还证明了在疾病复发时 KRAS 异常的持续性或新发性发生。针对 KRAS 的小分子抑制剂已经开发出来；然而，它们仅对携带 KRASG12C 突变的肿瘤具有选择性。因此，仍然需要开发针对其他肿瘤类型（包括 MM）中发现的 KRAS 突变事件的新型治疗方法。我们使用 AZD4785（一种有效的、选择性的反义寡核苷酸，可选择性地靶向和下调所有 KRAS 异构体）作为一种工具，在骨髓龛内环境中研究 MM 中 KRAS 沉默的继发功能后果，并证明其能够显著沉默 KRAS，从而抑制 MM 肿瘤的生长，无论是在体外还是体内，并证实 KRAS 是 MM 的驱动基因和治疗靶点。
