For many decades classical anti-tumor therapies included chemotherapy, radiation and surgery; however, in the last two decades, following the identification of the genomic drivers and main hallmarks of cancer, the introduction of therapies that target specific tumor-promoting oncogenic or non-oncogenic pathways, has revolutionized cancer therapeutics. Despite the significant progress in cancer therapy, clinical oncologists are often facing the primary impediment of anticancer drug resistance, as many cancer patients display either intrinsic chemoresistance from the very beginning of the therapy or after initial responses and upon repeated drug treatment cycles, acquired drug resistance develops and thus relapse emerges, resulting in increased mortality. Our attempts to understand the molecular basis underlying these drug resistance phenotypes in pre-clinical models and patient specimens revealed the extreme plasticity and adaptive pathways employed by tumor cells, being under sustained stress and extensive genomic/proteomic instability due to the applied therapeutic regimens. Subsequent efforts have yielded more effective inhibitors and combinatorial approaches (e.g. the use of specific pharmacologic inhibitors with immunotherapy) that exhibit synergistic effects against tumor cells, hence enhancing therapeutic indices. Furthermore, new advanced methodologies that allow for the early detection of genetic/epigenetic alterations that lead to drug chemoresistance and prospective validation of biomarkers which identify patients that will benefit from certain drug classes, have started to improve the clinical outcome. This review discusses emerging principles of drug resistance to cancer therapies targeting a wide array of oncogenic kinases, along with hedgehog pathway and the proteasome and apoptotic inducers, as well as epigenetic and metabolic modulators. We further discuss mechanisms of resistance to monoclonal antibodies, immunomodulators and immune checkpoint inhibitors, potential biomarkers of drug response/drug resistance, along with possible new therapeutic avenues for the clinicians to combat devastating drug resistant malignancies. It is foreseen that these topics will be major areas of focused multidisciplinary translational research in the years to come.

几十年来，经典的抗肿瘤疗法包括化学疗法，放射疗法和外科手术。然而，在过去的二十年中，在确定了基因组驱动因素和癌症的主要标志之后，针对靶向特定肿瘤促进致癌或非致癌途径的疗法的引入彻底改变了癌症疗法。尽管癌症治疗取得了重大进展，但由于许多癌症患者从治疗开始或在最初反应后以及反复药物治疗周期后就表现出内在的化学耐药性，因此临床肿瘤学家常常面临抗癌药耐药性的主要障碍。发生并因此出现复发，导致死亡率增加。我们试图了解临床前模型和患者标本中这些耐药表型的分子基础的尝试揭示了肿瘤细胞所采用的极端可塑性和适应性途径，由于所采用的治疗方案，它们承受着持续的压力和广泛的基因组/蛋白质组不稳定。随后的努力产生了更有效的抑制剂和组合方法（例如在免疫疗法中使用特定的药物抑制剂），这些抑制剂和组合方法对肿瘤细胞表现出协同作用，从而提高了治疗指数。此外，新的先进方法可以及早发现导致药物化学耐药性的遗传/表观遗传学改变，并可以对生物标志物进行前瞻性验证，从而鉴定出将从某些药物类别中受益的患者，已经开始改善临床结局。这篇综述讨论了针对多种致癌激酶的癌症疗法的耐药性的新兴原理，以及刺猬蛋白途径，蛋白酶体和凋亡诱导剂，以及表观遗传和代谢调节剂。我们进一步讨论了对单克隆抗体，免疫调节剂和免疫检查点抑制剂的耐药性机制，潜在的药物反应/耐药性生物标志物，以及为临床医生抗击毁灭性耐药性恶性肿瘤的可能新治疗途径。可以预见的是，这些主题将成为未来几年跨学科翻译研究的重点领域。以及刺猬通路，蛋白酶体和凋亡诱导剂，以及表观遗传和代谢调节剂。我们进一步讨论了对单克隆抗体，免疫调节剂和免疫检查点抑制剂的耐药性机制，潜在的药物反应/耐药性生物标志物，以及为临床医生抗击毁灭性耐药性恶性肿瘤的可能新治疗途径。可以预见的是，这些主题将成为未来几年跨学科翻译研究的重点领域。以及刺猬通路，蛋白酶体和凋亡诱导剂，以及表观遗传和代谢调节剂。我们进一步讨论了对单克隆抗体，免疫调节剂和免疫检查点抑制剂的耐药性机制，潜在的药物反应/耐药性生物标志物，以及为临床医生抗击毁灭性耐药性恶性肿瘤的可能新治疗途径。可以预见的是，这些主题将成为未来几年跨学科翻译研究的重点领域。以及为临床医生抗击毁灭性耐药性恶性肿瘤的可能的新治疗途径。可以预见的是，这些主题将成为未来几年跨学科翻译研究的重点领域。以及为临床医生抗击毁灭性耐药性恶性肿瘤的可能的新治疗途径。可以预见的是，这些主题将成为未来几年跨学科翻译研究的重点领域。