{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T23:50:43Z","timestamp":1790898643857,"version":"4.1.0"},"reference-count":520,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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\u2013drug 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.<\/jats:p>","DOI":"10.3390\/molecules31071195","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T00:19:32Z","timestamp":1775434772000},"page":"1195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Molecularly Targeted Therapies in Oncology: Mechanisms, Resistance, and Combination Strategies"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9665-1065","authenticated-orcid":false,"given":"Klaudia","family":"Giercuszkiewicz-Ha\u015bnik","sequence":"first","affiliation":[{"name":"Department of Systems Biology and Engineering, Silesian University of Technology, 44-100 Gliwice, Poland"},{"name":"Centre of Biotechnology, Silesian University of Technology, 44-100 Gliwice, Poland"},{"name":"Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5389-1079","authenticated-orcid":false,"given":"Beata","family":"Morak-M\u0142odawska","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4144-990X","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Jele\u0144","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1002\/cncr.34743","article-title":"Top Advances of the Year: Precision Oncology","volume":"129","author":"Desai","year":"2023","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11795549241298541","DOI":"10.1177\/11795549241298541","article-title":"Cancer Biomarkers and Precision Oncology: A Review of Recent Trends and Innovations","volume":"18","author":"AlDoughaim","year":"2024","journal-title":"Clin. 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