Hermansen Johanne U, Athanasiadis Paschalis, Yin Yanping, Rise Anne-Sofie F, Arribas Alberto J, Cascione Luciano, Russnes Hege G, Helland Åslaug, Mato Anthony R, Bertoni Francesco, Tjønnfjord Geir E, Aittokallio Tero, Skånland Sigrid S
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
K. G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Cell Death Dis. 2025 Jul 23;16(1):555. doi: 10.1038/s41419-025-07884-7.
Treatment of B-cell malignancies with the PI3K inhibitor (PI3Ki) idelalisib often results in high toxicity and resistance, with limited treatment alternatives for relapsed/refractory patients since idelalisib is recommended as a later or last line therapy. To investigate resistance mechanisms and identify alternative treatments, we studied functional phenotypes of idelalisib-resistant B-cell malignancy models. The idelalisib-resistant KARPAS1718 model remained sensitive to Bcl-2 inhibitors (Bcl-2i), whereas the resistant VL51 model showed reduced sensitivity compared to parental cells. Sensitivity correlated with phosphorylation and expression of the Bcl-2 family members Bcl-2 and Bim. Target addiction scoring revealed high dependence on the proteasome, and proteasome inhibitors (PI) were effective across models and in primary chronic lymphocytic leukemia (CLL) cells, independently of their PI3Ki- or Bcl-2i-sensitivities. PI treatment consistently upregulated Bim and Mcl-1, while Bcl-2 increased in KARPAS1718 and CLL cells. Bcl-2i plus PI combinations led to an additive effect in these models. A multi-refractory CLL patient in the IMPRESS-Norway trial (NCT04817956) treated with Bcl-2i plus PI showed initial clinical improvement but relapsed within four months. Treatment induced Bim and Mcl-1 upregulation and reduced cytotoxic CD8 T-cell and CD56 NK-cell populations. Our findings suggest that PIs may overcome resistance to targeted therapies, and warrant further studies to optimize clinical responses.
使用PI3K抑制剂（PI3Ki）idelalisib治疗B细胞恶性肿瘤通常会导致高毒性和耐药性，由于idelalisib被推荐作为二线或最后一线治疗，复发/难治性患者的治疗选择有限。为了研究耐药机制并确定替代治疗方法，我们研究了idelalisib耐药B细胞恶性肿瘤模型的功能表型。idelalisib耐药的KARPAS1718模型对Bcl-2抑制剂（Bcl-2i）仍敏感，而耐药的VL51模型与亲代细胞相比敏感性降低。敏感性与Bcl-2家族成员Bcl-2和Bim的磷酸化及表达相关。靶点成瘾评分显示对蛋白酶体高度依赖，蛋白酶体抑制剂（PI）在各模型及原发性慢性淋巴细胞白血病（CLL）细胞中均有效，与它们对PI3Ki或Bcl-2i的敏感性无关。PI治疗持续上调Bim和Mcl-1，而KARPAS1718和CLL细胞中的Bcl-2增加。在这些模型中，Bcl-2i加PI联合使用产生了相加效应。在IMPRESS-挪威试验（NCT04817956）中，一名接受Bcl-2i加PI治疗的多难治性CLL患者最初临床症状改善，但在四个月内复发。治疗诱导Bim和Mcl-1上调，并减少了细胞毒性CD8 T细胞和CD56 NK细胞群体。我们的研究结果表明，PI可能克服对靶向治疗的耐药性，值得进一步研究以优化临床反应。
