Weißbach Susann, Heredia-Guerrero Sofia Catalina, Barnsteiner Stefanie, Großhans Lukas, Bodem Jochen, Starz Hanna, Langer Christian, Appenzeller Silke, Knop Stefan, Steinbrunn Torsten, Rost Simone, Einsele Hermann, Bargou Ralf Christian, Rosenwald Andreas, Stühmer Thorsten, Leich Ellen
Institute of Pathology, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany.
Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany.
Cancers (Basel). 2020 Feb 16;12(2):455. doi: 10.3390/cancers12020455.
Approximately 20% of multiple myeloma (MM) cases harbor a point mutation in . However, there is still no final consent on whether -mutations are associated with disease outcome. Specifically, no data exist on whether -mutations have an impact on survival of MM patients at diagnosis in the era of novel agents. Direct blockade of KRAS for therapeutic purposes is mostly impossible, but recently a mutation-specific covalent inhibitor targeting KRAS entered into clinical trials. However, other hotspot-mutations exist in MM patients, including the less common exon-4 mutations. For the current study, the coding regions of were deep-sequenced in 80 newly diagnosed MM patients, uniformely treated with three cycles of bortezomib plus dexamethasone and cyclophosphamide (VCD)-induction, followed by high-dose chemotherapy and autologous stem cell transplantation. Moreover, the functional impact of KRAS and the exon-4 mutations p.A146T and p.A146V on different survival pathways was investigated. Specifically, KRAS, KRAS, KRAS, and KRAS were overexpressed in HEK293 cells and the KRAS MM cell lines JJN3 and OPM2 using lentiviral transduction and the Sleeping Beauty vector system. Even though -mutations were not correlated with survival, all KRAS-mutants were found capable of potentially activating MEK/ERK- and sustaining PI3K/AKT-signaling in MM cells.
约20%的多发性骨髓瘤（MM）病例在 中存在点突变。然而，关于 -突变是否与疾病预后相关仍未达成最终共识。具体而言，在新型药物时代，尚无关于 -突变对MM患者诊断时生存情况有无影响的数据。出于治疗目的直接阻断KRAS大多是不可能的，但最近一种靶向KRAS的突变特异性共价抑制剂已进入临床试验。然而，MM患者中还存在其他热点突变，包括不太常见的外显子4突变。在本项研究中，对80例新诊断的MM患者的 编码区进行了深度测序，这些患者均接受了三个周期的硼替佐米加地塞米松及环磷酰胺（VCD）诱导治疗，随后进行了大剂量化疗和自体干细胞移植。此外，还研究了KRAS以及外显子4突变p.A146T和p.A146V对不同生存途径的功能影响。具体而言，利用慢病毒转导和睡美人载体系统在HEK293细胞以及KRAS MM细胞系JJN3和OPM2中过表达KRAS、KRAS、KRAS和KRAS。尽管 -突变与生存无关，但发现所有KRAS突变体均能够在MM细胞中潜在激活MEK/ERK并维持PI3K/AKT信号传导。
