Jul 2026· International Journal of Pharmaceutical and Bio-Medical Science· 0 citations
TL;DR
This report systematically reviews the structural development, validation pathways, and regulatory mechanisms of next-generation oncology therapeutics and highlights clinical milestones and regulatory approvals from 2025 and 2026, including the landmark PROTAC vepdegestrant.
Abstract
The oncology landscape is undergoing a profound paradigm shift from broad-spectrum cytotoxic chemotherapies to highly selective, mechanism-driven precision medicine. This report systematically reviews the structural development, validation pathways, and regulatory mechanisms of next-generation oncology therapeutics. Modern precision oncology focuses on the targetable oncogenic drivers of malignant transformation—including epidermal growth factor receptor (EGFR) exon 20 insertions, human epidermal growth factor receptor 2 (HER2) mutations, Kirsten rat sarcoma virus oncogene (KRAS) G12C, and estrogen receptor 1 (ESR1) mutations—via small-molecule kinase inhibitors, antibody-drug conjugates (ADCs) featuring stable linkers and topoisomerase I payloads, and proteolysis-targeting chimeras (PROTACs). We highlight clinical milestones and regulatory approvals from 2025 and 2026, including the landmark PROTAC vepdegestrant, bispecific antibodies such as zenocutuzumab, and novel combinations like teclistamab with daratumumab.
These breakthroughs have validated direct KRAS inhibition as an effective therapeutic strategy, however, durable clinical responses remain limited by intrinsic and acquired resistance, pathway reactivation, tumour heterogeneity, and the lack of effective therapies for non-G12C KRAS mutations.
Pasham Uma, Dandotikar Neha, R. Manisha et al.· International Journal of Inn...· 0 citations
ABSTRACT Introduction The discovery of epidermal growth factor receptor (EGFR) mutations has deeply reshaped the treatment of non-small cell lung cancer (NSCLC). Throughout the last years, third-generation tyrosine kinase inhibitor (TKI) osimertinib in monotherapy has been the standard of care; however, resistance limits durable responses, necessitating novel combinations and sequencing strategies. Areas covered This review discusses recent advances in EGFR-targeted therapies within the molecular landscape of classical and uncommon EGFR mutations, focusing on frontline intensification strategies in metastatic disease—specifically TKI combinations with chemotherapy (FLAURA2) or bispecific antibodies (MARIPOSA)—and emerging post-progression strategies to overcome acquired resistance mechanisms. A comprehensive literature search (January 2021–March 2026) was conducted via PubMed, and recent major oncology conference proceedings (ASCO, ESMO, WCLC, ELCC) and clinical trial registries for ongoing studies. Expert opinion The therapeutic landscape is shifting from a uniform frontline TKI monotherapy approach toward biomarker-driven, risk-stratified, intensification. High-risk patients (e.g. TP53 co-mutations, L858R) derive significant benefit from combination regimens, whereas mono-TKI remains appropriate for favorable prognostic subgroups. Future progress relies on validating predictive biomarkers—particularly circulating tumor DNA (ctDNA) dynamics—to guide adaptive treatment strategies, balancing efficacy gains against toxicity and costs, while ensuring equitable global access to novel therapies.
L. Lucente, Lucrezia Barcellini, B. Ramella Pollone et al.· Expert Opinion on Pharmacoth...· 0 citations
ABSTRACT
Recent advances in breast cancer management have transformed treatment across molecular subtypes and expanded the role of precision oncology. Hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-positive (HER2-positive), HER2-low, and triple-negative breast cancer (TNBC) each demonstrate distinct biologic behavior requiring tailored therapeutic strategies. In HR-positive disease, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and next-generation selective estrogen receptor degraders have improved survival, while HER2-directed antibody-drug conjugates (ADCs) have expanded treatment options beyond traditional HER2-positive disease. HER2-low disease has recently emerged as a therapeutically actionable HER2-expression category, addressing a previously limited treatment space. In TNBC, immunotherapy and ADCs have broadened therapeutic options for historically difficult-to-treat disease. Advances in genomic profiling, including next-generation sequencing and circulating tumor DNA testing, allow clinicians to identify biomarkers to guide targeted therapy selection. As treatment complexity increases, APPs play an essential role in implementing precision oncology through patient education, toxicity management, genomic counseling, and clinical trial coordination. This review summarizes current treatment strategies across breast cancer subtypes, highlights emerging therapies, and emphasizes the expanding APP role.
Whitney Tobin· JAAPA : official journal of...· 0 citations
Breast cancer remains a leading cause of morbidity and mortality among women worldwide, necessitating innovative therapeutic strategies to overcome drug resistance and tumor heterogeneity. Breast cancer is a heterogeneous disease in which dysregulated tyrosine kinase signaling drives proliferation, survival, metastasis, and resistance. Tyrosine kinase inhibitors (TKIs) are pivotal targeted agents in breast cancer therapy, owing to their ability to modulate critical signaling pathways implicated in cancer progression. This review summarizes medicinal-chemistry strategies for designing small-molecule TKIs, integrating binding-mode classifications with scaffold selection and structure-guided optimization. Representative advances include HER2-selective, dual-RTK approaches such as EGFR/VEGFR-2 and EGFR/HER2 designs that enhance activity and overcome resistance. Emerging strategies, such as lapatinib-based PROTACs, demonstrate effective EGFR/HER2 degradation and strong antiproliferative activity in HER2-driven models, and have expanded beyond the HER family to include targets such as c-MET, FGFR, BTK, FAK, SRC, and JAK, highlighting their potential against the aggressive triple-negative breast cancer subtype. Studies featuring reversible and irreversible inhibitors, multi-targeted ligands, and covalent kinase inhibitors targeting BC are presented. These efforts underscore the importance of integrating scaffolds from promising candidate and clinically approved drugs to advance next-generation kinase inhibitors targeting breast cancer subtypes, thereby overcoming challenges and improving structural optimization outcomes.
Tamer A Elwaie, M. Aref, Hamed I. Ali· RSC Advances· 1 citation
Immunotherapy has revolutionized the treatment landscape of breast cancer, particularly for triple-negative breast cancer (TNBC), yet primary and acquired resistance remain formidable obstacles limiting durable clinical benefit. This review provides a comprehensive update on recent advances in breast cancer immunotherapy, with a focused emphasis on the molecular and cellular mechanisms driving treatment resistance and emerging strategies to overcome them. We dissect tumor-intrinsic resistance pathways, including loss of tumor antigens, defects in antigen processing and presentation machinery, insensitivity to interferon-γ signaling, metabolic reprogramming, and epigenetic dysregulation. Tumor-extrinsic mechanisms, such as infiltration of immunosuppressive cells, abnormal angiogenesis, extracellular matrix remodeling, and FGF/FGFR genomic amplification, are highlighted as key barriers to effective immune checkpoint blockade. Emerging evidence implicates novel resistance mediators, including the DUSP22-LGALS1 axis, THSD4-driven T cell exclusion, and the MTDH-SND1 complex impairing antigen presentation, etc. We critically evaluate current strategies to surmount resistance, encompassing combination regimens with chemotherapy, targeted therapies, radiotherapy, and novel immunomodulators. The review also addresses challenges in managing immune-related adverse events, controversies surrounding patient selection biomarkers, and the urgent need for optimized efficacy evaluation systems beyond RECIST criteria. Finally, we discuss future directions, including novel immune checkpoints, microbiome modulation, artificial intelligence-assisted decision-making, and innovative trial designs. By integrating mechanistic insights with clinical evidence, this review provides a framework for understanding and overcoming immunotherapy resistance, advancing the paradigm from "effective" to "precise" immuno-oncology in breast cancer.
Jia-Mei Wang, Yi Zhou, Feifei Li et al.· Critical reviews in oncology...· 0 citations
Breast cancer encompasses molecularly distinct subtypes with divergent oncogenic dependencies, each amenable to precision therapeutic intervention. Over the past decade, clinically meaningful advances have reshaped breast cancer management: antibody-drug conjugates (ADCs) have expanded actionable HER2 expression thresholds to include HER2-low and HER2-ultralow populations; cyclin-dependent kinase (CDK) 4/6 inhibitors have become standard-of-care in hormone receptor-positive disease; and immune checkpoint blockade has established durable responses in a defined subset of triple-negative breast cancer (TNBC). Nevertheless, therapeutic resistance remains the central unresolved obstacle to durable benefit. Here, we synthesize current evidence on the signaling architecture underlying targeted therapy across breast cancer subtypes and propose a four-layer network topology model of resistance integrating: (i) canonical pathway reactivation; (ii) receptor tyrosine kinase (RTK) reprogramming; (iii) non-coding RNA (ncRNA) regulatory circuits; and (iv) epigenetic plasticity coupled with tumor microenvironment (TME) co-evolution. We explicitly stratify the discussed mechanisms into three evidence tiers-clinically actionable, plausibly translational, and exploratory-to avoid conflating preclinical observations with validated biomarkers. We critically evaluate FDA-approved and emerging agents within this framework, identify knowledge gaps, and outline future directions-including liquid biopsy-guided adaptive therapy, multi-omic resistance profiling, and biologically rational combination strategies-together with their feasibility constraints related to toxicity, sequencing, cost, and biomarker validation.
Yadong Wang, Maona Zhang, Xuefang Zhang et al.· Critical reviews in oncology...· 1 citation