Liu Ying, Wu Lei, Lu Hong, Wu En, Ni Jun, Zhou Xiaorong
Department of Immunology, Nantong University, School of Medicine, Nantong, Jiangsu 226001, China.
Department of Physical Therapy, Shanghai Yangzhi Rehabilitation Hospital, Shanghai 201619, China.
J Oncol. 2021 Nov 23;2021:2721466. doi: 10.1155/2021/2721466. eCollection 2021.
KRAS inhibitors have shown promising efficacy in early clinical trials, but drug resistance compromises their long-term benefits. Therefore, it is critical to understand the mechanisms of drug resistance and to design appropriate combinatory treatments to improve efficacy.
To understand the comprehensive mechanisms of drug resistance, we treated lung cancer cells with KRAS inhibitors for different periods and performed transcriptional profiling and signaling analysis to identify critical factors and pathways that drive drug tolerance and resistance. We also evaluated several drug combinations in vitro and in vivo to identify potentially effective therapeutics.
We found that the feedback activation of multiple receptor tyrosine kinases (RTKs) may have cooperatively induced intrinsic and adaptive resistance to KRAS inhibitors. Notably, continuous KRAS inhibition induced a multidrug-resistant phenotype, implying that upfront combinatory treatment might be required to treat this group of patients. We also demonstrated that concurrently targeting multiple nodes in the RTK/RAS/RAF/MEK/ERK axis improved the efficacy of KRAS inhibitors, mainly by suppressing the reactivation of the mitogen-activated protein kinase (MAPK) pathway. Moreover, the combined use of HSP90 and KRAS inhibitors effectively induced tumor regression in lung adenocarcinoma models in vitro and in vivo.
Together, our findings revealed mechanisms underlying KRAS inhibitors resistance and provided novel candidate combinatory strategies to improve their anticancer activity.
KRAS抑制剂在早期临床试验中已显示出有前景的疗效，但耐药性损害了它们的长期益处。因此，了解耐药机制并设计合适的联合治疗方案以提高疗效至关重要。
为了解耐药的综合机制，我们用KRAS抑制剂处理肺癌细胞不同时间段，并进行转录谱分析和信号分析，以确定驱动药物耐受性和耐药性的关键因素和途径。我们还在体外和体内评估了几种药物组合，以确定潜在有效的治疗方法。
我们发现多种受体酪氨酸激酶（RTK）的反馈激活可能协同诱导了对KRAS抑制剂的内在和适应性耐药。值得注意的是，持续的KRAS抑制诱导了多药耐药表型，这意味着可能需要 upfront 联合治疗来治疗这组患者。我们还证明，同时靶向RTK/RAS/RAF/MEK/ERK轴中的多个节点可提高KRAS抑制剂的疗效，主要是通过抑制丝裂原活化蛋白激酶（MAPK）途径的重新激活。此外，HSP90和KRAS抑制剂的联合使用在体外和体内肺腺癌模型中均有效诱导肿瘤消退。
总之，我们的研究结果揭示了KRAS抑制剂耐药的机制，并提供了新的候选联合策略以提高其抗癌活性。
