Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, Baltimore, Maryland.
Cancer Res Commun. 2024 Sep 1;4(9):2308-2319. doi: 10.1158/2767-9764.CRC-24-0020.
Constitutively active mutant EGFR is one of the major oncogenic drivers in non-small cell lung cancer (NSCLC). Targeted therapy using EGFR tyrosine kinase inhibitor (TKI) is a first-line option in patients that have metastatic or recurring disease. However, despite the high response rate to TKI, most patients have a partial response, and the disease eventually progresses in 10 to 19 months. It is believed that drug-tolerant cells that survive TKI exposure during the progression-free period facilitate the emergence of acquired resistance. Thus, targeting the drug-tolerant cells could improve the treatment of NSCLC with EGFR mutations. We demonstrated here that EGFR-mutant patient-derived xenograft tumors responded partially to osimertinib despite near-complete inhibition of EGFR activation. Signaling in AKT/mTOR and MAPK pathways could be reactivated shortly after initial inhibition. As a result, many tumor cells escaped drug killing and regained growth following about 35 days of continuous osimertinib dosing. However, when an antibody to hepatoma-derived growth factor (HDGF) was given concurrently with osimertinib, tumors showed complete or near-complete responses. There was significant prolongation of progression-free survival of tumor-bearing mice as well. IHC and Western blot analysis of tumors collected in the early stages of treatment suggest that increased suppression of the AKT/mTOR and MAPK pathways could be a mechanism that results in enhanced efficacy of osimertinib when it is combined with an anti-HDGF antibody.
These results suggest that HDGF could be critically involved in promoting tolerance to TKI in patient-derived xenografts of NSCLC tumors. Blocking HDGF signaling could be a potential means to enhance EGFR-targeted therapy of NSCLC that warrants further advanced preclinical and clinical studies.
组成性激活的突变 EGFR 是 NSCLC 中的主要致癌驱动因素之一。在转移性或复发性疾病患者中，使用 EGFR 酪氨酸激酶抑制剂（TKI）的靶向治疗是一线选择。然而，尽管 TKI 的反应率很高，但大多数患者只有部分反应，并且疾病最终会在 10 到 19 个月内进展。人们认为，在无进展期间 TKI 暴露后存活的耐药细胞促进了获得性耐药的出现。因此，靶向耐药细胞可能会改善 EGFR 突变 NSCLC 的治疗效果。我们在这里证明，尽管 EGFR 激活几乎完全被抑制，但 EGFR 突变的患者衍生异种移植肿瘤对奥希替尼仍有部分反应。AKT/mTOR 和 MAPK 通路的信号在最初抑制后不久即可重新激活。结果，许多肿瘤细胞在连续奥希替尼给药约 35 天后逃脱了药物杀伤并恢复了生长。然而，当同时给予肝癌衍生生长因子（HDGF）抗体和奥希替尼时，肿瘤表现出完全或近乎完全的反应。荷瘤小鼠的无进展生存期也显著延长。治疗早期收集的肿瘤的 IHC 和 Western blot 分析表明，增加 AKT/mTOR 和 MAPK 通路的抑制可能是奥希替尼与抗 HDGF 抗体联合使用时增强疗效的一种机制。
这些结果表明，HDGF 可能在促进 NSCLC 患者衍生异种移植肿瘤对 TKI 的耐药性方面发挥关键作用。阻断 HDGF 信号可能是增强 EGFR 靶向治疗 NSCLC 的一种潜在手段，值得进一步进行高级的临床前和临床研究。
