Mechanisms of Drug Resistance in Cancer: Overcoming Barriers with Novel Pharmacological Strategies

Drug resistance remains the foremost challenge to durable cancer control. Tumors evolve dynamic mechanisms to evade therapy through target mutations, pathway redundancy, metabolic reprogramming, epigenetic plasticity, and altered uptake or efflux. Beyond the cell-intrinsic changes, the tumor microenvironment—characterized by hypoxia, acidosis, dense stroma, aberrant vasculature, and immune exclusion—creates pharmacokinetic and biophysical barriers that further restrict drug efficacy. These adaptive processes can generate multidrug resistance, reducing the lifespan of even the most sophisticated targeted and immuno-oncology agents.

The rapid expansion of molecular profiling, single-cell and spatial transcriptomics, functional proteomics, and advanced imaging now enables precise mapping of resistance trajectories across therapeutic classes. However, translating these mechanistic insights into clinically viable pharmacological strategies remains a critical gap. This Research Topic aims to bridge that divide by gathering experimental and translational contributions that dissect resistance biology and propose rational pharmacological interventions.

This Research Topic seeks to define and overcome resistance mechanisms in cancer therapy through a pharmacology-driven framework. Specifically, it aims to:

•Characterize molecular, cellular, and microenvironmental determinants of therapeutic resistance.
•Develop and test novel pharmacological strategies—including covalent or allosteric inhibitors, rational drug combinations, and PK/PD-guided regimens—that can prevent or reverse resistance.
•Advance delivery innovations such as tumor-targeted nanosystems and biomimetic carriers to improve bioavailability and selectivity.
•Identify predictive biomarkers using genomics, proteomics, metabolomics, and imaging to enable precision dosing and patient stratification.

The overarching goal is to foster a mechanistic understanding that guides the next generation of pharmacological interventions—spanning covalent and allosteric inhibitors, multitarget strategies, and smart delivery systems—to overcome resistance and extend clinical benefit.

We invite submissions that investigate the mechanisms of intrinsic and acquired resistance across small molecules, biologics, antibody–drug conjugates, radiopharmaceuticals, and cell/gene therapies. Contributions may include studies elucidating the interplay between genetic, epigenetic, and metabolic rewiring in resistance; design and optimization of resistance-evading agents; and pharmacokinetic/pharmacodynamic (PK/PD) modeling approaches that inform dose, schedule, and sequencing strategies. We also encourage studies integrating nanomedicine, tumor-targeting platforms, and combination regimens to enhance drug penetration, selectivity, and therapeutic index.

We also invite contributions on the following themes:

•Mechanisms of intrinsic and acquired resistance including target alteration, adaptive signaling, metabolic reprogramming, and phenotypic plasticity.
•Pharmacological and delivery strategies to circumvent resistance (covalent/allosteric inhibitors, polypharmacology, nanoscale delivery).
•Integration of omics and imaging-based biomarkers for resistance prediction and response monitoring.
•PK/PD modeling and simulation approaches to guide dose optimization and sequence scheduling.
•Translational studies demonstrating synergy between small molecules, biologics, and immuno/radio/gene therapies.

We welcome Original Research, Reviews, Mini Reviews, and Methods articles. Multidisciplinary collaborations linking pharmacology, systems biology, medicinal chemistry, bioengineering, and clinical oncology are particularly encouraged.

The Research Topic will not consider purely prognostic studies, side-effect management reports, or traditional medicine approaches that lack mechanistic pharmacological evaluation.