Molecular profiling and personalized targeting in PDAC: implications of KRAS, BRCA, SMAD4, and emerging biomarkers

Authors

  • Made Ayu Kurniati Atmaja Faculty of Medicine, Udayana University Author
  • Anak Agung Gede Cahya Wedanta Faculty of Medicine, Udayana University Author
  • I Gede Bayu Bagus Ananda Radiasa Faculty of Medicine, Udayana University Author
  • I Gede Aswin Parisya Sasmana Faculty of Medicine, Udayana University Author
  • I Gede Putu Supadmanaba Biochemistry Department, Faculty of Medicine, Udayana University Author

Keywords:

pancreatic ductal adenocarcinoma, KRAS, BRCA1/2, SMAD4, PARP inhibitors, synthetic lethality, precision oncology, liquid biopsy, molecular profiling

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid tumors. This review synthesizes current understanding of the principal molecular drivers of PDAC, namely KRAS, BRCA1/2, and SMAD4 together with emerging biomarkers, and examines how this knowledge is being translated into personalized therapeutic strategies. A narrative review was conducted using the PubMed database to identify articles published between January 2016 and June 2026 relevant to molecular profiling and personalized targeting in PDAC. Articles were screened against predefined inclusion and exclusion criteria and synthesized thematically. KRAS, mutated in over 90% of cases (predominantly G12D), has shifted from an undruggable target to one addressed by mutation-selective and pan-RAS inhibitors, although adaptive resistance through receptor tyrosine kinase reactivation and YAP/TAZ signaling limits response durability. BRCA1/2 mutations (5–10%) confer homologous recombination deficiency and sensitivity to PARP inhibitors through synthetic lethality, with olaparib improving progression-free survival in the POLO trial. SMAD4 inactivation (50–55%), a late-stage event, functions as a prognostic biomarker associated with aggressive, metastatic disease and poorer survival. Emerging biomarkers, including circulating tumor DNA, exosomal GPC1, MSI-H/dMMR status, tumor mutational burden, rare fusions (NTRK, NRG1, FGFR2), and the Hippo-YAP/TAZ pathway, are broadening precision oncology options. KRAS, BRCA1/2, and SMAD4 each provide distinct therapeutic and prognostic information in PDAC.

Author Biographies

  • Made Ayu Kurniati Atmaja, Faculty of Medicine, Udayana University

    Faculty of Medicine, Udayana University

  • Anak Agung Gede Cahya Wedanta, Faculty of Medicine, Udayana University

    Faculty of Medicine, Udayana University

  • I Gede Bayu Bagus Ananda Radiasa, Faculty of Medicine, Udayana University

    Faculty of Medicine, Udayana University

  • I Gede Aswin Parisya Sasmana, Faculty of Medicine, Udayana University

    Faculty of Medicine, Udayana University

  • I Gede Putu Supadmanaba, Biochemistry Department, Faculty of Medicine, Udayana University

    Biochemistry Department, Faculty of Medicine, Udayana University

References

1. Singhal, A., Styers, H. C., Rub, J., Li, Z., Torborg, S. R., Kim, J. Y., Grbovic-Huezo, O., Feng, H., Tarcan, Z. C., Ozkan, H. S., Hallin, J., Basturk, O., Yaeger, R., Christensen, J. G., Betel, D., Yan, Y., Chio, I. I. C., de Stanchina, E., & Tammela, T. (2024). A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer. Cancer Discovery, 14(11), 2122–2134. https://doi.org/10.1158/2159-8290.CD-24-0740

2. Moyana, T., & Merz, V. (2025). Editorial: Molecular markers for pancreatic cancers: new technologies and applications in the clinical practice. In Frontiers in Oncology (Vol. 15). Frontiers Media SA. https://doi.org/10.3389/fonc.2025.1651566

3. Lloyd, E. G., Jihad, M., Manansala, J. S., Li, W., Cheng, P. S. W., Mucciolo, G., Zaccaria, M., Teles, S. P., Henríquez, J. A., Harish, S., Brais, R., Ashworth, S., Luo, W., Johnson, P. M., Veghini, L., Vallespinos, M., Corbo, V., & Biffi, G. (2025). SMAD4 and KRAS Status Shapes Cancer Cell–Stromal Cross-Talk and Therapeutic Response in Pancreatic Cancer. Cancer Research, 85(8), 1368–1389. https://doi.org/10.1158/0008-5472.CAN-24-2330

4. Wang, Y., Yu, T., Zhao, Z., Li, X., Song, Y., He, Y., Zhou, Y., Li, P., An, L., & Wang, F. (2024). SMAD4 Limits PARP1 dependent DNA Repair to Render Pancreatic Cancer Cells Sensitive to Radiotherapy. Cell Death & Disease, 15(11), 818. https://doi.org/10.1038/s41419-024-07210-7

5. Caban, M., & Małecka-Wojciesko, E. (2023). Gaps and Opportunities in the Diagnosis and Treatment of Pancreatic Cancer. In Cancers (Vol. 15, Number 23). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/cancers15235577

6. Wei, D., Wang, L., Zuo, X., Maitra, A., & Bresalier, R. S. (2024). A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer. In Clinical Cancer Research (Vol. 30, Number 4, pp. 655–662). American Association for Cancer Research Inc. https://doi.org/10.1158/1078-0432.CCR-23-2098

7. Franck, C., Müller, C., Rosania, R., Croner, R. S., Pech, M., & Venerito, M. (2020). Advanced pancreatic ductal adenocarcinoma: Moving forward. In Cancers (Vol. 12, Number 7, pp. 1–19). MDPI AG. https://doi.org/10.3390/cancers12071955

8. Stefanoudakis, D., Frountzas, M., Schizas, D., Michalopoulos, N. V., Drakaki, A., & Toutouzas, K. G. (2024). Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer. In Current Issues in Molecular Biology (Vol. 46, Number 4, pp. 2827–2844). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/cimb46040177

9. Duan, X., Zhang, T., Feng, L., de Silva, N., Greenspun, B., Wang, X., Moyer, J., Martin, M. L., Chandwani, R., Elemento, O., Leach, S. D., Evans, T., Chen, S., & Pan, F. C. (2024). A pancreatic cancer organoid platform identifies an inhibitor specific to mutant KRAS. Cell Stem Cell, 31(1), 71-88.e8. https://doi.org/10.1016/j.stem.2023.11.011

10. Ouyang, W., Hao, J., Niu, Q., Douglass, E., Beusch, C. M., Gordon, D. E., Hall, M., Moffit, R., Du, Y., & Mo, X. (2025). Identification and Characterization of a TGF-β-Independent SMAD4–NFATc1–STAT3 Regulatory Axis. Journal of Molecular Cell Biology. https://doi.org/10.1093/jmcb/mjaf028

11. Kowalewski, A., Szylberg, Ł., Saganek, M., Napiontek, W., Antosik, P., & Grzanka, D. (2018). Emerging strategies in BRCA-positive pancreatic cancer. In Journal of Cancer Research and Clinical Oncology (Vol. 144, Number 8, pp. 1503–1507). Springer Verlag. https://doi.org/10.1007/s00432-018-2666-9

12. Xiao, M., Yang, J., Dong, M., Mao, X., Pan, H., Lei, Y., Tong, X., Yu, X., Yu, X., & Shi, S. (2024). NLRP4 renders pancreatic cancer resistant to olaparib through promotion of the DNA damage response and ROS-induced autophagy. Cell Death and Disease, 15(8). https://doi.org/10.1038/s41419-024-06984-0

13. Xiao, M., Yu, X., & Shi, S. (2024). NLRP4 drives olaparib resistance in pancreatic cancer. In Autophagy Reports (Vol. 3, Number 1). Informa UK Ltd. https://doi.org/10.1080/27694127.2024.2422729

14. Pergolizzi, R. G., & Brower, S. T. (2024). Molecular Targets for the Diagnosis and Treatment of Pancreatic Cancer. In International Journal of Molecular Sciences (Vol. 25, Number 19). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/ijms251910843

15. Reshkin, S. J., Cardone, R. A., & Koltai, T. (2024). Genetic Signature of Human Pancreatic Cancer and Personalized Targeting. In Cells (Vol. 13, Number 7). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/cells13070602

16. Stickler, S., Rath, B., & Hamilton, G. (2024). Targeting KRAS in pancreatic cancer. In Oncology Research (Vol. 32, Number 5, pp. 799–805). Tech Science Press. https://doi.org/10.32604/or.2024.045356

17. Rozengurt, E., & Eibl, G. (2026). Pancreatic cancer: molecular pathogenesis and emerging therapeutic strategies. In Signal Transduction and Targeted Therapy (Vol. 11, Number 1). Springer Nature. https://doi.org/10.1038/s41392-025-02499-y

18. Dilly, J., Hoffman, M. T., Abbassi, L., Li, Z., Paradiso, F., Parent, B. D., Hennessey, C. J., Jordan, A. C., Morgado, M., Dasgupta, S., Uribe, G. A., Yang, A., Kapner, K. S., Hambitzer, F. P., Qiang, L., Feng, H., Geisberg, J., Wang, J., Evans, K. E., … Aguirre, A. J. (2024). Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer. Cancer Discovery, 14(11), 2135–2161. https://doi.org/10.1158/2159-8290.CD-24-0177

19. Zhou, K., Liu, Y., Tang, C., & Zhu, H. (2025). Pancreatic Cancer: Pathogenesis and Clinical Studies. In MedComm (Vol. 6, Number 4). John Wiley and Sons Inc. https://doi.org/10.1002/mco2.70162

20. Singh, H. M., Bailey, P., Hübschmann, D., Berger, A. K., Neoptolemos, J. P., Jäger, D., Siveke, J., & Springfeld, C. (2021). Poly(ADP-ribose) polymerase inhibition in pancreatic cancer. In Genes Chromosomes and Cancer (Vol. 60, Number 5, pp. 373–384). John Wiley and Sons Inc. https://doi.org/10.1002/gcc.22932

21. Masi, M., Poppi, L., Previtali, V., Nelson, S. R., Wynne, K., Varignani, G., Falchi, F., Veronesi, M., Albanesi, E., Tedesco, D., De Franco, F., Ciamarone, A., Myers, S. H., Ortega, J. A., Bagnolini, G., Ferrandi, G., Farabegoli, F., Tirelli, N., Di Stefano, G., … Cavalli, A. (2025). Investigating synthetic lethality and PARP inhibitor resistance in pancreatic cancer through enantiomer differential activity. Cell Death Discovery, 11(1). https://doi.org/10.1038/s41420-025-02382-3

22. D’Empaire Altimari, D. M., Bevere, M., Espinet, E., Martineau, Y., Giovannetti, E., & Sánchez-Arévalo Lobo, V. J. (2026). Molecular subtypes in pancreatic cancer: from academic promise to clinical reality. In Molecular Cancer (Vol. 25, Number 1). BioMed Central Ltd. https://doi.org/10.1186/s12943-026-02614-9

23. Ahmed, S., Bradshaw, A. D., Gera, S., Zahidunnabi Dewan, M., & Xu, R. (2017). The TGF-β/Smad4 signaling pathway in pancreatic carcinogenesis and its clinical significance. In Journal of Clinical Medicine (Vol. 6, Number 1). MDPI. https://doi.org/10.3390/jcm6010005

24. Lee, D. K. C., Chen, K., Loke, R., Li, X., Liubart, D., Saffi, G. T., Chow, J. T. S., Melo, C. M. P., To, L., & Salmena, L. (2025). ITGAV and SMAD4 influence the progression and clinical outcome of pancreatic ductal adenocarcinoma. Molecular Oncology, 19(11), 3342–3359. https://doi.org/10.1002/1878-0261.70080

25. Qian, Y., Gong, Y., Fan, Z., Luo, G., Huang, Q., Deng, S., Cheng, H., Jin, K., Ni, Q., Yu, X., & Liu, C. (2020). Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma. In Journal of Hematology and Oncology (Vol. 13, Number 1). BioMed Central Ltd. https://doi.org/10.1186/s13045-020-00958-3

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Published

2026-04-25

Issue

Vol. 2 No. 1 (2026)

Section

REVIEW