Mahfoudhi Emna, Ricordel Charles, Lecuyer Gwendoline, Mouric Cécile, Lena Hervé, Pedeux Rémy
Univ Rennes, Institut Nationale de la Santé et de la Recherche Médicale (INSERM), COSS (Chemistry Oncogenesis Stress Signaling), UMR_S 1242, Centre de Lutte Contre le Cancer (CLOC) Eugène Marquis, Rennes, France.
Centre Hospitalier Universitaire de Rennes, Service de Pneumologie, Université de Rennes 1, Rennes, France.
Front Oncol. 2022 Apr 7;12:853501. doi: 10.3389/fonc.2022.853501. eCollection 2022.
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are currently recommended as first-line treatment for advanced non-small-cell lung cancer (NSCLC) with -activating mutations. Third-generation (3rd G) EGFR-TKIs, including osimertinib, offer an effective treatment option for patients with NSCLC resistant 1st and 2nd EGFR-TKIs. However, the efficacy of 3rd G EGFR-TKIs is limited by acquired resistance that has become a growing clinical challenge. Several clinical and preclinical studies are being carried out to better understand the mechanisms of resistance to 3rd G EGFR-TKIs and have revealed various genetic aberrations associated with molecular heterogeneity of cancer cells. Studies focusing on epigenetic events are limited despite several indications of their involvement in the development of resistance. Preclinical models, established in most cases in a similar manner, have shown different prevalence of resistance mechanisms from clinical samples. Clinically identified mechanisms include EGFR mutations that were not identified in preclinical models. Thus, NRAS genetic alterations were not observed in patients but have been described in cell lines resistant to 3rd G EGFR-TKI. Mainly, resistance to 3rd G EGFR-TKI in preclinical models is related to the activation of alternative signaling pathways through tyrosine kinase receptor (TKR) activation or to histological and phenotypic transformations. Yet, preclinical models have provided some insight into the complex network between dominant drivers and associated events that lead to the emergence of resistance and consequently have identified new therapeutic targets. This review provides an overview of preclinical studies developed to investigate the mechanisms of acquired resistance to 3rd G EGFR-TKIs, including osimertinib and rociletinib, across all lines of therapy. In fact, some of the models described were first generated to be resistant to first- and second-generation EGFR-TKIs and often carried the T790M mutation, while others had never been exposed to TKIs. The review further describes the therapeutic opportunities to overcome resistance, based on preclinical studies.
表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂（TKIs）目前被推荐作为具有激活突变的晚期非小细胞肺癌（NSCLC）的一线治疗药物。第三代（3G）EGFR-TKIs，包括奥希替尼，为对第一代和第二代EGFR-TKIs耐药的NSCLC患者提供了一种有效的治疗选择。然而，第三代EGFR-TKIs的疗效受到获得性耐药的限制，这已成为一个日益严峻的临床挑战。目前正在进行多项临床和临床前研究，以更好地了解对第三代EGFR-TKIs耐药的机制，并揭示了与癌细胞分子异质性相关的各种基因畸变。尽管有迹象表明表观遗传事件参与了耐药的发生，但专注于表观遗传事件的研究仍然有限。在大多数情况下以类似方式建立的临床前模型显示，耐药机制的发生率与临床样本不同。临床确定的机制包括在临床前模型中未发现的EGFR突变。因此，NRAS基因改变在患者中未观察到，但在对第三代EGFR-TKI耐药的细胞系中已有描述。主要地，临床前模型中对第三代EGFR-TKI的耐药与通过酪氨酸激酶受体（TKR）激活的替代信号通路的激活或组织学和表型转化有关。然而，临床前模型为导致耐药出现的主要驱动因素和相关事件之间的复杂网络提供了一些见解，从而确定了新的治疗靶点。本综述概述了为研究对第三代EGFR-TKIs（包括奥希替尼和罗西替尼）获得性耐药机制而开展的临床前研究，涵盖了所有治疗线。事实上，所描述的一些模型最初是为了对第一代和第二代EGFR-TKIs耐药而构建的，通常携带T790M突变，而其他模型从未接触过TKIs。本综述还基于临床前研究描述了克服耐药的治疗机会。
