Aug 2026· Biochimica et biophysica acta. Reviews on cancer· pp.
189684
· 0 citations· 238 references
Medicine
TL;DR
This comprehensive review highlights BMBC resistance mechanisms, drawing from preclinical models, clinical studies, and genomic analyses, and highlights the potential for personalized, multi-targeted approaches to improve patient outcomes in BMBC.
Abstract
Brain-metastatic breast cancer (BMBC) is a severe complication of advanced breast cancer, affecting 15-30% of metastatic patients, particularly those with HER2-positive or triple-negative subtypes, and is associated with dismal prognosis and median survival under 12 months. Therapeutic resistance, driven by the central nervous system's sanctuary role, poses a major barrier to effective treatment, often resulting in discordant intracranial versus extracranial responses. This comprehensive review highlights BMBC resistance mechanisms, drawing from preclinical models, clinical studies, and genomic analyses. Key drivers include genetic/epigenetic alterations, BBB-mediated drug exclusion via efflux transporters, and microenvironmental interactions with astrocytes and immune cells that promote survival signaling. Additional factors encompass cancer stem cell plasticity/dormancy enabling therapy evasion, metabolic reprogramming and extracellular matrix remodeling that shields tumor from drugs. We highlight how these interconnected pathways create a protective niche for metastatic cells. Promising strategies to overcome resistance include BBB-penetrant agents, antibody-drug conjugates, nanomedicine, and combination therapies targeting the tumor microenvironment and epigenetics. By integrating mechanistic insights with translational opportunities, this review emphasizes the potential for personalized, multi-targeted approaches to improve patient outcomes in BMBC.
Plastic features of BCSCs are summarized, their roles in metastasis and multidrug resistance, microenvironmental regulation and relevant therapeutic targeting strategies are summarized and progress toward subtype-specific combination approaches is indicated.
Mu-Yao Li, Ying Zhou, Xin-Qi Liu et al.· Cancer Advances· 0 citations
Triple-negative breast cancer remains an aggressive and biologically heterogeneous breast cancer subtype. Although the therapeutic landscape has expanded, durable disease control remains clinically challenging in many settings. Existing reviews often organize TNBC therapy by drug class or molecular subtype, which can obscure how treatment response is shaped by interacting biological layers. Here, we review current and emerging therapeutic strategies through a three-layer framework: tumor-cell-intrinsic vulnerabilities, the local immune and stromal microenvironment, and host-level systemic modifiers. We summarize established approaches, including chemotherapy, immune checkpoint blockade, antibody–drug conjugates and PARP inhibition in biomarker-defined settings, and distinguish them from maturing or exploratory strategies such as pathway-directed therapy, epigenetic modulation, anti-vascular combinations, regulated cell-death induction, cellular therapy, vaccines, microbiome-related interventions, liquid biopsy, AI-supported multiomics and adaptive trial designs. This framework integrates evidence level, disease stage, biomarker reliability and patient tolerance into treatment selection for TNBC precision therapy.
Zi-Xun Wang, Xi-Yu Liu, Yu-Xiao Wu et al.· Journal of Hematology & Onco...· 0 citations
A narrative review summarizes the major signaling pathways implicated in GBM pathogenesis, including EGFR, PI3K/AKT/mTOR, Wnt, and TGF-β signaling, while also discussing emerging therapeutic targets such as FGFR3–TACC3 fusions, regorafenib, and natural killer cell-based immunotherapy.
William W Li, J. Chen, Yiying Ma· Future Science OA· 0 citations
The integration of TME-targeted and individualized therapeutic strategies may offer promising prospects toward achieving durable clinical outcomes in breast cancer treatment.
P. Shankar, Gowthamarajan Kuppusamy, Apsara Unni et al.· Current Cancer Therapy Revie...· 0 citations
Breast cancer is the most frequently reported cancer in women, with high mortality and morbidity globally. Paclitaxel, doxorubicin, tamoxifen, cisplatin, and 5-fluorouracil are cornerstones of standard-of-care treatment for primary and advanced breast cancers, targeting distinct molecular mechanisms. However, the evolution of acquired resistance primarily leads to treatment failure and progression to metastasis, ultimately to patient mortality. Furthermore, their effectiveness is limited by potential toxicities in various organs. These limitations present an extreme challenge for the management of breast cancer at the advanced stage. This review uncovers recent updates on acquired resistance mechanisms toward standard-of-care treatments driven by deeply rooted heterogeneity and aggressive nature through direct counteracting of its core action, hyperactivation of survival pathways, silencing of core cell death pathways, derepressing the expression of multidrug resistance proteins, metabolic reprogramming, epigenetic modifications, and exosome-mediated horizontal transfer of resistance phenotype. In addition, we discuss recent updates on potential strategies to overcome resistance and toxicities induced by standard-of-care treatments. Ultimately, this review helps to identify novel strategies targeting pathways to reverse resistance and reduce toxicity in breast cancer patients.
Anuveda Sree Samudrala, G. P. Nagaraju, RamaRao Malla· Biochimica et biophysica act...· 0 citations
Multiple myeloma (MM) is a malignant plasma cell disorder, and despite substantial improvements in prognosis achieved through chemotherapy, immunotherapy, and autologous stem cell transplantation, most patients ultimately develop relapsed or refractory disease. Drug resistance (DR) is increasingly recognized as a dynamically evolving ecosystem shaped by tumor‐intrinsic plasticity and continuous remodeling of the bone marrow microenvironment (BMME), rather than as a single molecular lesion. This review summarizes the major mechanisms of resistance across key drug classes, including alterations in drug targets and signaling nodes, rewiring of apoptotic, proteostatic, and metabolic circuits, and BMME‐dependent protection. We highlight how these processes converge on a limited set of survival hubs and collectively raise the apoptotic threshold under therapeutic pressure. The key to overcoming DR is to conceptualize it as an evolving ecosystem, thereby enabling rational, mechanism‐based combination and sequencing strategies that may prolong progression‐free survival and move MM closer to a functional cure.
Yixuan Chen, Wen-Ming Huang, Mingxuan Tang et al.· Cell Biochemistry and Functi...· 0 citations
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