Molecularly Targeted Therapies in Oncology: Mechanisms, Resistance, and Combination Strategies

Targeted therapies are reshaping oncology by enabling treatment selection based on actionable molecular alterations, improving precision, and reducing unnecessary toxicity. This review provides an up-to-date overview of current targeted treatment modalities and the medicinal chemistry principles that support their discovery and optimization. We synthesize evidence on small-molecule and biologic strategies spanning receptor and non-receptor kinases and their major signaling axes (PI3K-AKT-mTOR and RAS-RAF-MEK-ERK), apoptosis regulation (BCL-2 family), DNA repair via poly(ADP-ribose) polymerase (PARP) inhibition, and epigenetic or metabolic targets including histone deacetylases (HDACs), bromodomain and extra-terminal proteins (BET), and mutant isocitrate dehydrogenases (IDH1/2). Across these areas, we summarize recurrent resistance mechanisms and the rationale for combination or sequential approaches. Biologic targeted therapy is discussed in parallel, including immune checkpoint blockade, antibody-drug conjugates, bispecific antibodies (BsAb), and cell therapies such as chimeric antigen receptor T cells, with emphasis on biomarker-guided patient stratification. Finally, we outline emerging directions beyond canonical nodes, including modulation of the p53-MDM2/MDM4 axis, ferroptosis control through AIFM2/FSP1, and innate immune pathways such as CD47-SIRPa and the stimulator of interferon genes (STING). Overall, the field is shifting from single-target inhibition toward integrated strategies that combine precise molecular targeting with an understanding of signaling network dynamics, resistance evolution, and therapeutic vulnerabilities.