Radiotherapy is frequently combined with chemotherapy, targeted therapy and immunotherapy to improve the efficacy of cancer treatment. Nevertheless, some radioresistant cancer cells seem to possess higher drug resistance, leading to failure of cancer treatment. Thus, it is crucial to explore the mechanisms of drug resistance in cancer RT. This review outlines molecular, cellular, and microenvironmental adaptations in cancer RT. These adaptations confer enhanced chemotherapy resistance in cancer cells surviving from ionizing radiation (IR). In addition, RT also activates oncogene signaling pathways, induces epigenetic remodeling and alters post-translational modifications, collectively driving resistance to targeted therapy. RT alters tumor intrinsic properties, promotes immunosuppressive effects and remodels TME, thus inducing immunotherapy resistance. Various emerging strategies including phytochemicals, small molecules, synthetic compounds, macromolecules, nanoparticles, photodynamic therapy (PDT), photothermal therapy (PTT), MicroRNA (miRNA) therapy, PROTACs, adoptive cell therapies, and engineered Salmonella, have been developed to overcome radioresistance and drug resistance in cancer RT. We highlight the importance of evaluating therapeutic effects and side effects of these emerging strategies. Through summarizing mechanisms and emerging strategies for drug resistance in cancer RT, this review aims to clarify obstacles in combined cancer treatment and guide future direction of research on cancer therapy.
Yang Chen, Chao-Yun Cai, Xiao-Cheng Xu et al.· Pharmacological Research· 0 citations
Antibody-drug conjugates (ADCs) are one of the most significant advancements in modern cancer therapeutics. Combining the target selectivity of monoclonal antibodies with the cytotoxic potential of payloads, ADCs effectively kill cancer cells and offer hope to patients with even refractory cancer types. Beyond simply increasing the number of therapeutic options available for cancer patients, ADCs have become a powerful frontline agent in overcoming multidrug resistance (MDR). As one of the most challenging obstacles to effective cancer care, MDR is mediated by ATP-binding cassette (ABC) transporter-mediated drug efflux, target-based mutations, and dysregulated apoptosis. The clinical success of ADCs specifically engineered to overcome MDR, including in heterogeneous tumors and cancer cells that exhibit bypass signaling, is well established. This is especially evident with trastuzumab deruxtecan (T-DXd) in HER2-low, HER2-positive, and HER2-mutant cancers; sacituzumab govitecan (SG) in TROP2-expressing triple-negative breast cancer (TNBC) and urothelial carcinoma; and enfortumab vedotin in Nectin-4-positive bladder cancer. By overcoming MDR, ADCs have enabled more effective treatment algorithms across multiple malignancies. Most importantly, the clinical application of ADCs has become inextricably linked to cancer genomics. HER2 testing has evolved from a two-tiered system to a continuous spectrum including HER2-ultralow, HER2-low, HER2-positive, and ERBB2-mutant categories. Each of these categories exhibits different eligibility guidelines for ADC patient selection. As cancer cells continue to evolve and develop resistance to even ADCs through mutations and variants, researchers and clinicians have used pharmacogenomics to predict ADC response and resistance. To define the genomic architecture of ADC-resistant tumor subpopulations, single-cell transcriptomic studies and liquid biopsy approaches are being used to enable real-time examination of the tumor genome during ADC therapy, thereby optimizing treatment and circumventing resistance driven by emerging mutations and variants. This review provides a comprehensive analysis of the molecular structure of ADCs, the pharmacological principles underlying their potent cytotoxic activity against MDR cancer cells, the genomic and transcriptomic biomarkers that guide ADC patient selection, and the emerging resistance mechanisms that will shape the next generation of promising ADC development.
Ryan Li, Xiang Chen, Qinguo Huang et al.· Cancer Letters· 0 citations
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