Drug Resistance in Targeted Cancer Treatment: Clinical Difficulties, Molecular Mechanisms, and Emerging Strategies

Year : 2026 | Volume : 17 | 01 | Page :
    By

    Bharath B,

  • Darshan G,

  • Hamsa Priya M,

  1. Student, Department of Pharmacy, Aditya Bangalore Institute of Pharmacy Education and Research, Bangalore, Karnataka, India
  2. Student, Department of Pharmacy, Aditya Bangalore Institute of Pharmacy Education and Research, Bangalore, Karnataka, India
  3. Student, Department of Pharmacy, Aditya Bangalore Institute of Pharmacy Education and Research, Bangalore, Karnataka, India

Abstract

Targeted cancer therapy, which selectively inhibits the molecular mechanisms responsible for tumor growth and development, has revolutionized modern oncology. Targeted therapies have lower systemic toxicity and better therapeutic efficacy when compared to traditional chemotherapy. However, the emergence of medication resistance often limits the long-term efficacy of these treatments, ultimately resulting in treatment failure and disease progression. Drug resistance develops through a number of intricate biological processes and can be innate or acquired. These mechanisms include pharmacokinetic changes that impact medication absorption and intracellular accumulation, tumor heterogeneity, epigenetic modifications, activation of alternative signaling pathways, genetic mutations in drug targets, and protection mediated by the tumor microenvironment. To improve treatment outcomes and create more potent anticancer therapies, it is crucial to comprehend these resistance pathways. The molecular and pharmacological mechanisms underlying resistance to the main kinds of targeted anticancer medicines, including as tyrosine kinase inhibitors, monoclonal antibodies, and hormone-targeted therapies, are thoroughly described in this article. The paper also covers new approaches to combat drug resistance, including combination therapy, next-generation targeted inhibitors, precision oncology guided by biomarkers, and sophisticated drug delivery methods, including formulations based on nanoparticles. Future targeted cancer treatments may be more long-lasting and successful if resistance mechanisms and novel therapeutic techniques are better understood.

Keywords: Pharmacogenomics, precision oncology, tyrosine kinase inhibitors, drug resistance, and targeted cancer treatment.

How to cite this article:
Bharath B, Darshan G, Hamsa Priya M. Drug Resistance in Targeted Cancer Treatment: Clinical Difficulties, Molecular Mechanisms, and Emerging Strategies. Research and Reviews: A Journal of Pharmaceutical Science. 2026; 17(01):-.
How to cite this URL:
Bharath B, Darshan G, Hamsa Priya M. Drug Resistance in Targeted Cancer Treatment: Clinical Difficulties, Molecular Mechanisms, and Emerging Strategies. Research and Reviews: A Journal of Pharmaceutical Science. 2026; 17(01):-. Available from: https://journals.stmjournals.com/rrjops/article=2026/view=239730


References

1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674.
2. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13(10):714–726.
3. Roskoski R. Properties of FDA-approved small molecule protein kinase inhibitors. Pharmacol Res. 2019;144:19–50.
4. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. 2017;376:629–640.
5. Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014;11:473–481.
6. Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5:219–234.
7. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005;205:275–292.
8. Housman G, Byler S, Heerboth S, et al. Drug resistance in cancer: an overview. Cancers (Basel). 2014;6:1769–1792.
9. Garraway LA, Jänne PA. Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov. 2012;2:214–226.
10. Sharma SV, Lee DY, Li B, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141:69–80.
11. Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature. 2019;575:299–309.
12. Dienstmann R, Rodon J, Tabernero J. Genomic medicine frontier in human solid tumors: prospects and challenges. J Clin Oncol. 2013;31:1874–1884.
13. Patel H, Pawara R, Pawara S, et al. Nanotechnology-based drug delivery systems in cancer therapy. J Drug Deliv Sci Technol. 2020;60:102097.
14. Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers. Nat Biotechnol. 2015;33:941–951.
15. Gottesman MM, Lavi O, Hall MD, Gillet JP. Toward a better understanding of the complexity of cancer drug resistance. Annu Rev Pharmacol Toxicol. 2016;56:85–102.
16. Swanton C. Intratumor heterogeneity: evolution through space and time. Cancer Res. 2012;72:4875–4882.
17. Meads MB, Gatenby RA, Dalton WS. Environment-mediated drug resistance. Nat Rev Cancer. 2009;9:665–674.
18. Klemm F, Joyce JA. Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol. 2015;25:198–213.
19. Relling MV, Evans WE. Pharmacogenomics in the clinic. Nature. 2015;526:343–350.
20. Tannock IF, Hickman JA. Limits to personalized cancer medicine. N Engl J Med. 2016;375:1289–1294.
21. Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013;501:338–345.
22. Wu P, Nielsen TE, Clausen MH. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol Sci. 2015;36:422–439.
23. Turner NC, Reis-Filho JS. Genetic heterogeneity and cancer drug resistance. Lancet Oncol. 2012;13:e178–e185.
24. Al-Lazikani B, Banerji U, Workman P. Combinatorial drug therapy for cancer in the post-genomic era. Nat Biotechnol. 2012;30:679–692.
25. De Mattos-Arruda L, Cortes J, Santarpia L, et al. Circulating tumor cells and cell-free DNA as tools for managing breast cancer. Nat Rev Clin Oncol. 2013;10:377–389.
26. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy. Clin Cancer Res. 2013;19:2240–2247.
27. Dienstmann R, Vermeulen L, Guinney J, Kopetz S, Tejpar S, Tabernero J. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer. 2017;17:79–92.

Ahead of Print Subscription Review Article
Volume 17
01
Received 14/03/2026
Accepted 29/03/2026
Published 31/03/2026
Publication Time 17 Days
38

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