Targeting AXL in NSCLC.
Targeting AXL in NSCLC.
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DOI：
10.2147/lctt.s305484
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Bivona TG
中科院分区：
文献类型：
--
作者：
Zaman A;Bivona TG
最先进的癌症精准医学方法涉及对化学和免疫学可解决的漏洞进行有针对性的灭活，这些漏洞通常会在患者中产生令人印象深刻的初始抗肿瘤反应。尽管如此，这些反应却被随之而来的治疗抵抗所掩盖。 AXL 是一种具有真正致癌能力的受体酪氨酸激酶，它与一系列具有不同病理生理学和细胞起源的癌症（包括非小细胞肺癌 (NSCLC)）的耐药性的出现有关。在这篇综述中，我们总结了正常稳态、致癌发展和治疗耐药期间的 AXL 生物学，重点关注 NSCLC。在 NSCLC 治疗耐药的背景下，我们描述了 AXL 在介导针对表皮生长因子受体 (EGFR) 以及其他显着癌基因和化疗药物的酪氨酸激酶抑制剂 (TKI) 耐药性中的作用。我们还讨论了目前对 AXL 在介导细胞生物学变量中的作用的理解，这些变量是治疗抵抗的重要调节剂，例如上皮间质转化 (EMT)、肿瘤微环境和肿瘤异质性。我们还对一系列有效的药理学工具进行了分类和讨论，这些工具正在出现，可以战略性地干扰 NSCLC 中 AXL 介导的耐药程序。最后，我们列举了当前和未来令人兴奋的针对 AXL 的精准医学方法以及这方面的挑战。我们强调，对 NSCLC 中 AXL 生物学的全面了解可能使我们能够预测和改进靶向治疗策略，例如通过多疗法方法，可能针对广泛的 NSCLC 亚型，以预防肿瘤进化和耐药性。
State-of-the-art cancer precision medicine approaches involve targeted inactivation of chemically and immunologically addressable vulnerabilities that often yield impressive initial anti-tumor responses in patients. Nonetheless, these responses are overshadowed by therapy resistance that follows. AXL, a receptor tyrosine kinase with bona fide oncogenic capacity, has been associated with the emergence of resistance in an array of cancers with varying pathophysiology and cellular origins, including in non-small-cell lung cancers (NSCLCs). Here in this review, we summarize AXL biology during normal homeostasis, oncogenic development and therapy resistance with a focus on NSCLC. In the context of NSCLC therapy resistance, we delineate AXL’s role in mediating resistance to tyrosine kinase inhibitors (TKIs) deployed against epidermal growth factor receptor (EGFR) as well as other notable oncogenes and to chemotherapeutics. We also discuss the current understanding of AXL’s role in mediating cell-biological variables that function as important modifiers of therapy resistance such as epithelial to mesenchymal transition (EMT), the tumor microenvironment and tumor heterogeneity. We also catalog and discuss a set of effective pharmacologic tools that are emerging to strategically perturb AXL mediated resistance programs in NSCLC. Finally, we enumerate ongoing and future exciting precision medicine approaches targeting AXL as well as challenges in this regard. We highlight that a holistic understanding of AXL biology in NSCLC may allow us to predict and improve targeted therapeutic strategies, such as through polytherapy approaches, potentially against a broad spectrum of NSCLC sub-types to forestall tumor evolution and drug resistance.