Santoni Matteo, Mollica Veronica, Rizzo Alessandro, Massari Francesco
Medical Oncology Unit, Macerata Hospital, Macerata, Italy.
Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Cancer Treat Rev. 2025 Feb;133:102881. doi: 10.1016/j.ctrv.2025.102881. Epub 2025 Jan 6.
Immune-based combinations are the cornerstone of the first-line treatment of metastatic renal cell carcinoma patients, leading to outstanding outcomes. Nevertheless, primary resistance and disease progression is a critical clinical challenge. To properly address this issue, it is pivotal to understand the mechanisms of resistance to immunotherapy and tyrosine kinase inhibitors, that tumor eventually develop under treatment. In this review of the literature, we aim at exploring resistance mechanisms arising in patients treated with first-line immune-based combinations in order to understand the biological pattern that should be investigated to overcome them. In more detail, mechanisms of resistance to nivolumab and pembrolizumab are divided into intrinsic to cancer cells and extrinsic (stromal or immune cells). Regarding axitinib, the increased expression of Nuclear protein 1 (NUPR1) or decreased levels of insulin receptor (INSR) characterize resistant cells. The secretion of non-VEGF pro-angiogenic factors, such as PDGF-BB, IL-1β, MMP-9, Gro-α, IL-8, IL-6, and CCL-2, can lead to resistance to cabozantinib. The reactivation of pathways previously targeted by lenvatinib or the activation of alternative pathways, such as EGFR-PAK2-ERK pathway, underlie the development of resistance to lenvatinib. Exploring resistance mechanism that arise during first-line therapy can lead to the development of treatment strategy able to overcome them in order to improve duration of response and patients outcomes.
基于免疫的联合疗法是转移性肾细胞癌患者一线治疗的基石，带来了出色的治疗效果。然而，原发性耐药和疾病进展是一项严峻的临床挑战。为了妥善解决这一问题，了解肿瘤在治疗过程中最终产生的对免疫疗法和酪氨酸激酶抑制剂的耐药机制至关重要。在这篇文献综述中，我们旨在探索接受一线基于免疫的联合疗法治疗的患者中出现的耐药机制，以便了解为克服这些机制应研究的生物学模式。更详细地说，对纳武利尤单抗和帕博利珠单抗的耐药机制分为癌细胞内在机制和外在机制（基质细胞或免疫细胞）。对于阿昔替尼，核蛋白1（NUPR1）表达增加或胰岛素受体（INSR）水平降低是耐药细胞的特征。非VEGF促血管生成因子如血小板衍生生长因子BB（PDGF-BB）、白细胞介素-1β（IL-1β）、基质金属蛋白酶-9（MMP-9）、生长调节致癌基因α（Gro-α）、白细胞介素-8（IL-8）、白细胞介素-6（IL-6）和趋化因子配体2（CCL-2）的分泌可导致对卡博替尼耐药。先前被乐伐替尼靶向的通路重新激活或替代通路如表皮生长因子受体-丝氨酸/苏氨酸蛋白激酶2-细胞外信号调节激酶（EGFR-PAK2-ERK）通路的激活是对乐伐替尼产生耐药的基础。探索一线治疗期间出现的耐药机制可导致开发能够克服这些机制的治疗策略，从而改善缓解持续时间和患者的治疗效果。
