PO.ET03.06 · 实验与分子治疗
鉴定TROP2作为KRAS G12C抑制中的适应性耐药机制及其治疗靶向
Identification of TROP2 as an adaptive resistance mechanism in KRAS G12C inhibition and its therapeutic targeting
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：KRAS突变发生于高达30%的非小细胞肺癌（NSCLC）中，主要位于密码子12和13。KRAS G12C是最常见的变异，约占KRAS突变型NSCLC的40%。KRAS G12C抑制剂sotorasib和adagrasib已引入临床实践用于KRAS G12C突变型NSCLC，但其临床获益仍然有限。这一有限疗效的一个重要机制是适应性耐药，与受体酪氨酸激酶等膜相关信号分子的激活有关，后者进而重新激活KRAS下游信号并降低药物持久性。鉴定驱动适应性耐药的因素对于开发有效的联合策略至关重要。
目的：鉴定介导NSCLC中对KRAS G12C抑制剂适应性耐药的分子靶点，并评估克服耐药的新型治疗方法。
方法与结果：为阐明对KRAS G12C抑制剂适应性耐药的机制，我们在H1373细胞中短期暴露sotorasib后进行RNA测序，发现TACSTD2（TROP2）是一个其mRNA表达早期上调的基因。为检验其功能相关性，我们在H358、H2122和H1373细胞中用siRNA沉默TROP2，发现TROP2敲低通过流式细胞术增加sotorasib诱导的凋亡，并增强对PI3K-AKT信号的抑制。与体外发现一致，sotorasib在H1373异种移植肿瘤中增加了TROP2表达。此外，用shRNA抑制TROP2增强了sotorasib在体内的抗肿瘤作用。另外，在LU65异种移植模型中，与sotorasib单药相比，sotorasib与抗TROP2抗体-药物偶联物datopotamab deruxtecan的联合实现了更持久的肿瘤缩小。最后，我们利用人工智能（AI）模型分析非小细胞肺癌（NSCLC）患者临床标本中的TROP2免疫组化评分，并研究其与预后的关联。
结论：TROP2靶向治疗是克服NSCLC中对KRAS G12C抑制剂适应性耐药的一种有前景的策略，值得进一步临床研究。
查看英文原文 English abstract
Background: KRAS mutations occur in up to 30% of non-small cell lung cancer (NSCLC), predominantly at codons 12 and 13. KRAS G12C, the most frequent variant, accounts for approximately 40% of KRAS-mutated NSCLC. The KRAS G12C inhibitors sotorasib and adagrasib have been introduced into clinical practice for KRAS G12C-mutated NSCLC, but their clinical benefit remains limited. One important mechanism for this limited efficacy is adaptive resistance, linked to activation of membrane-associated signaling molecules such as receptor tyrosine kinases, which in turn reactivate KRAS downstream signaling and reduce drug durability. Identifying factors driving adaptive resistance is critical for developing effective combination strategies.
Objective: To identify molecular targets mediating adaptive resistance to KRAS G12C inhibitors in NSCLC and evaluate novel therapeutic approaches to overcome resistance.
Methods and Results: To elucidate the mechanism of adaptive resistance to KRAS G12C inhibitors, we performed RNA sequencing after short-term sotorasib exposure in H1373 cells and found TACSTD2 (TROP2) was a gene with early upregulation of its mRNA expression. To test its functional relevance, we silenced TROP2 by siRNA in H358, H2122, and H1373 cells and found that TROP2 knockdown increased sotorasib-induced apoptosis by flow cytometry and enhanced suppression of PI3K-AKT signaling. Consistent with the in vitro findings, sotorasib increased TROP2 expression in H1373 xenograft tumors. Furthermore, TROP2 suppression by shRNA enhanced the antitumor effect of sotorasib in vivo. In addition, in LU65 xenograft model, the combination of sotorasib with the anti-TROP2 antibody-drug conjugate datopotamab deruxtecan achieved more durable tumor shrinkage compared with sotorasib monotherapy. Finally, we utilized an artificial intelligence (AI) model to analyze TROP2 immunohistochemistry scores in clinical specimens from patients with non-small cell lung cancer (NSCLC) and investigated the association with prognosis.
Conclusion: TROP2-targeted therapy represents a promising strategy to overcome adaptive resistance to KRAS G12C inhibitors in NSCLC and warrants further clinical investigation.
利益披露 Disclosure
M. Kashima, None..
H. Kitai, None..
Y. Yoshida, None..
Y. Ishida, None..
Y. Sato, None..
D. Morinaga, None..
K. Tsuji, None..
S. Ito, None.
K. C. Hatanaka,
Sakura Finetek ).
Sekisui Medical ).
Chugai Pharma ).
T. Kobayashi,
Biomy Inc. Employment.
Y. Shinomiya, None.
T. Konishi,
Biomy Inc. g., Board of Directors, non-salaried role), Stock.
Y. Hatanaka,
Eli Lilly ).
Daiichi Sankyo ).
Chugai Pharma ).
Bosto Gene ).
Konica Minolta ).
NEC corp ).
Biomy ).
CURED ).
AstraZeneca Other, honoraria, lecture fee.
Daiichi Sankyo Other, honoraria, lecture fee.
J. Sakakibara-Konishi, None.
S. Konno,
CHUGAI PHARMACEUTICAL CO., LTD. ).