Department of Biomedicine, University Hospital Basel, Basel, Switzerland; Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy; Department of Surgery and Translational Medicine, University of Florence, Florence, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China; and Department of Mechanisms of Cancer, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Physiol Rev. 2016 Jul;96(3):805-29. doi: 10.1152/physrev.00024.2015.
Although modern therapeutic strategies have brought significant progress to cancer care in the last 30 years, drug resistance to targeted monotherapies has emerged as a major challenge. Aberrant regulation of multiple physiological signaling pathways indispensable for developmental and metabolic homeostasis, such as hyperactivation of pro-survival signaling axes, loss of suppressive regulations, and impaired functionalities of the immune system, have been extensively investigated aiming to understand the diversity of molecular mechanisms that underlie cancer development and progression. In this review, we intend to discuss the molecular mechanisms of how conventional physiological signal transduction confers to acquired drug resistance in cancer patients. We will particularly focus on protooncogenic receptor kinase inhibition-elicited tumor cell adaptation through two major core downstream signaling cascades, the PI3K/Akt and MAPK pathways. These pathways are crucial for cell growth and differentiation and are frequently hyperactivated during tumorigenesis. In addition, we also emphasize the emerging roles of the deregulated host immune system that may actively promote cancer progression and attenuate immunosurveillance in cancer therapies. Understanding these mechanisms may help to develop more effective therapeutic strategies that are able to keep the tumor in check and even possibly turn cancer into a chronic disease.
尽管在过去的 30 年中，现代治疗策略为癌症治疗带来了重大进展，但靶向单药治疗的耐药性已成为一个主要挑战。多个对发育和代谢稳态至关重要的生理信号通路的异常调节，如促生存信号轴的过度激活、抑制性调节的丧失以及免疫系统功能受损，已经被广泛研究，旨在了解导致癌症发生和发展的分子机制的多样性。在这篇综述中，我们旨在讨论常规生理信号转导如何赋予癌症患者获得性耐药的分子机制。我们将特别关注原癌受体激酶抑制引发的肿瘤细胞适应，通过两条主要的核心下游信号级联，即 PI3K/Akt 和 MAPK 途径。这些途径对于细胞生长和分化至关重要，并且在肿瘤发生过程中经常过度激活。此外，我们还强调了失调的宿主免疫系统的新兴作用，它可能积极促进癌症进展并削弱癌症治疗中的免疫监视。了解这些机制可能有助于开发更有效的治疗策略，能够控制肿瘤并使癌症成为慢性疾病。
