Research advances in the role of cell cycle dysregulation in the development and progression of pancreatic ductal adenocarcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHENG Ye ¹ , MOU Jiangwei ¹ , WU Sheng ¹ , ZHANG Yanjun ^1,2 ,  ZHU Kexiang ^1,3

1. The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, P. R. China;
2. Department of General Practice, The First Hospital of Lanzhou University, Lanzhou 730000, P. R. China;
3. Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, P. R. China;

Corresponding?author：

ZHU Kexiang, Email: flexzhu6910@163.com

Keywords：

pancreatic ductal adenocarcinoma; cell cycle dysregulation; tumor microenvironment; immunosuppression; targeted therapy

DOI：

10.7507/1007-9424.202511068

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the research progress on cell cycle dysregulation in pancreatic ductal adenocarcinoma (PDAC), to explore its roles in PDAC development, malignant biological behavior, and therapeutic resistance, and to provide references for the optimization of cell cycle-related targeted therapeutic strategies. Methods Relevant studies published in recent years on the role of cell cycle dysregulation in the development of PDAC were systematically retrieved and reviewed. Results Cell cycle dysregulation is involved in multiple stages of PDAC development and progression, promoting sustained tumor cell proliferation, therapeutic resistance, and malignant progression. Therapeutic strategies targeting key cell cycle regulators, including CDK4/6, ATR, CHK1, and WEE1, have shown promising potential. However, the efficacy of monotherapy remains limited, and further optimization of combination strategies and patient selection is still needed. Conclusions Cell cycle dysregulation is an important biological basis for PDAC development and therapeutic resistance, and it also represents a potential therapeutic entry point. Further clarification of its molecular mechanisms and optimization of biologically guided combination strategies may provide new directions for improving PDAC treatment.

Citation： ZHENG Ye, MOU Jiangwei, WU Sheng, ZHANG Yanjun, ZHU Kexiang. Research advances in the role of cell cycle dysregulation in the development and progression of pancreatic ductal adenocarcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2026, 33(5): 711-718. doi: 10.7507/1007-9424.202511068 Copy

1.	Mannucci A, Goel A. Advances in pancreatic cancer early diagnosis, prevention, and treatment: the past, the present, and the future. CA Cancer J Clin, 2026, 76(1): e70035. doi: 10.3322/caac.70035.
2.	Stoop TF, Javed AA, Oba A, et al. Pancreatic cancer. Lancet, 2025, 405(10485): 1182-1202.
3.	Engeland K. Cell cycle regulation: p53-p21-RB signaling. Cell Death Differ, 2022, 29(5): 946-960.
4.	Lee JJ, Yeh JJ. Updates in molecular profiling of pancreatic ductal adenocarcinoma. Surg Clin North Am, 2024, 104(5): 939-950.
5.	Stefanoudakis D, Frountzas M, Schizas D, et al. Significance of TP53, CDKN2A, SMAD4 and KRAS in pancreatic cancer. Curr Issues Mol Biol, 2024, 46(4): 2827-2844.
6.	Jazieh K, Tsai J, Solomon S, et al. Identification of candidate alterations mediating KRASG12C inhibitor resistance in advanced colorectal and pancreatic cancers. Clin Cancer Res, 2025, 31(5): 899-906.
7.	Tiede KOM, Teixeira MF, Moura M, et al. Efficacy and safety signals from early-phase studies of KRAS inhibition in pancreatic cancer. Sci Rep, 2026, 16(1): 13189. doi: 10.1038/s41598-026-40757-3.
8.	Mercadante AA, Kasi A. Genetics, cancer cell cycle phases. Treasure Island (FL).: StatPearls Publishing, 2026. https://www.ncbi.nlm.nih.gov/books/NBK563158/.
9.	Pellarin I, Dall’Acqua A, Favero A, et al. Cyclin-dependent protein kinases and cell cycle regulation in biology and disease. Signal Transduct Target Ther, 2025, 10(1): 11. doi: 10.1038/s41392-024-02080-z.
10.	Shalaby A, Sadri N, Xue Y. Molecular pathology of pancreatic ductal adenocarcinoma. Cancers (Basel), 2025, 17(21): 3549. doi: 10.3390/cancers17213549.
11.	Rozengurt E, Eibl G. Pancreatic cancer: molecular pathogenesis and emerging therapeutic strategies. Signal Transduct Target Ther, 2026, 11(1): 6. doi: 10.1038/s41392-025-02499-y.
12.	Linehan A, O’Reilly M, McDermott R, et al. Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies. Front Med (Lausanne), 2024, 11: 1369136. doi: 10.3389/fmed.2024.1369136.
13.	Casacuberta-Serra S, González-Larreategui í, Capitán-Leo D, et al. MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer. Signal Transduct Target Ther, 2024, 9(1): 205. doi: 10.1038/s41392-024-01907-z.
14.	Palanivel C, Madduri LSV, Hein AL, et al. PR55α-controlled protein phosphatase 2A inhibits p16 expression and blocks cellular senescence induction by γ-irradiation. Aging (Albany NY), 2024, 16(5): 4116-4137.
15.	Yakar D?, Bozk?rl? BO, Ceyhan GO. Genetic landscape of pancreatic cancer: a narrative review. Chin Clin Oncol, 2022, 11(1): 5. doi: 10.21037/cco-22-4.
16.	Rahnamay Farnood P, Danesh Pazhooh R, Asemi Z, et al. DNA damage response and repair in pancreatic cancer development and therapy. DNA Repair (Amst), 2021, 103: 103116. doi: 10.1016/j.dnarep.2021.103116.
17.	Tsanov KM, Barriga FM, Ho YJ, et al. SMAD4 induces opposite effects on metastatic growth from pancreatic tumors depending on the organ of residence. Nat Cancer, 2025, 6(11): 1839-1856.
18.	Baba AB, Rah B, Bhat GR, et al. Transforming growth factor-beta (TGF-β) signaling in cancer-a betrayal within. Front Pharmacol, 2022, 13: 791272. doi: 10.3389/fphar.2022.791272.
19.	Dreyer SB, Upstill-Goddard R, Paulus-Hock V, et al. Targeting DNA damage response and replication stress in pancreatic cancer. Gastroenterology, 2021, 160(1): 362-377.
20.	Kumar NA, Manasa P, Chandrasekaran J. Revisiting CHK1 and WEE1 kinases as therapeutic targets in cancer. Biochim Biophys Acta Rev Cancer, 2025, 1880(6): 189482. doi: 10.1016/j.bbcan.2025.189482.
21.	Kciuk M, Wanke K, Marciniak B, et al. Targeting ATR-CHK1 and ATM-CHK2 axes in pancreatic cancer-a comprehensive review of literature. Int J Mol Sci, 2026, 27(3): 1152. doi: 10.3390/ijms27031152.
22.	Hayashi H, Uemura N, Zhao L, et al. Biological significance of YAP/TAZ in pancreatic ductal adenocarcinoma. Front Oncol, 2021, 11: 700315. doi: 10.3389/fonc.2021.700315.
23.	Hartupee C, Nagalo BM, Chabu CY, et al. Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target. Front Immunol, 2024, 15: 1287459. doi: 10.3389/fimmu.2024.1287459.
24.	Zhu Q, Wei X, Qu Z, et al. The roles of cell cycle proteins in regulating the tumor immune microenvironment. Genes Dis, 2025, 13(1): 101706. doi: 10.1016/j.gendis.2025.101706.
25.	Maleki EH, Bahrami AR, Matin MM. Cancer cell cycle heterogeneity as a critical determinant of therapeutic resistance. Genes Dis, 2023, 11(1): 189-204.
26.	Liu YP, Zheng CC, Huang YN, et al. Molecular mechanisms of chemo- and radiotherapy resistance and the potential implications for cancer treatment. MedComm (2020), 2021, 2(3): 315-340.
27.	Sigirli S, Karakas D. Fibrotic fortresses and therapeutic frontiers: pancreatic stellate cells and the extracellular matrix in pancreatic cancer. Cancer Med, 2025, 14(11): e70788. doi: 10.1002/cam4.70788.
28.	Sherman MH, Beatty GL. Tumor microenvironment in pancreatic cancer pathogenesis and therapeutic resistance. Annu Rev Pathol, 2023, 18: 123-148.
29.	Zhang J, Wang Y, Wang L, et al. Pancreatic ductal adenocarcinoma chemoresistance: from metabolism reprogramming to novel treatment. Chin Med J (Engl), 2024, 137(4): 408-420.
30.	Kpeglo D, Haddrick M, Knowles MA, et al. Modelling and breaking down the biophysical barriers to drug delivery in pancreatic cancer. Lab Chip, 2024, 24(4): 854-868.
31.	Liu C, Li C, Liu Y. The role of metabolic reprogramming in pancreatic cancer chemoresistance. Front Pharmacol, 2023, 13: 1108776. doi: 10.3389/fphar.2022.1108776.
32.	Dalin S, Sullivan MR, Lau AN, et al. Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance. Cancer Res, 2019, 79(22): 5723-5733.
33.	Qin Q, Yu R, Eriksson JE, et al. Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma therapy: challenges and opportunities. Cancer Lett, 2024, 591: 216859. doi: 10.1016/j.canlet.2024.216859.
34.	Zhang H, Cao K, Xiang J, et al. Hypoxia induces immunosuppression, metastasis and drug resistance in pancreatic cancers. Cancer Lett, 2023, 571: 216345. doi: 10.1016/j.canlet.2023.216345.
35.	Ju Y, Xu D, Liao MM, et al. Barriers and opportunities in pancreatic cancer immunotherapy. NPJ Precis Oncol, 2024, 8(1): 199. doi: 10.1038/s41698-024-00681-z.
36.	Matsumoto R, Tanoue K, Nakayama C, et al. Strategies to target the tumor-associated macrophages in the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma. Cancers (Basel), 2025, 17(18): 3090. doi: 10.3390/cancers17183090.
37.	Joseph AM, Al Aiyan A, Al-Ramadi B, et al. Innate and adaptive immune-directed tumour microenvironment in pancreatic ductal adenocarcinoma. Front Immunol, 2024, 15: 1323198. doi: 10.3389/fimmu.2024.1323198.
38.	Fahey CG, Cordova AF, Gedeon PC, et al. Targeting STING to generate therapeutic anti-tumor immunity. Cancer Cell, 2026, 44(2): 260-280.
39.	Costamagna A, Ghiglione N, Martini M. The molecular logic of early metastasis in pancreatic cancer: crosstalk between tumor and microenvironment. Front Cell Dev Biol, 2025, 13: 1726581. doi: 10.3389/fcell.2025.1726581.
40.	Maddipati R. Metastatic heterogeneity in pancreatic cancer: mechanisms and opportunities for targeted intervention. J Clin Invest, 2025, 135(14): e191943. doi: 10.1172/JCI191943.
41.	Tindall RR, Bailey-Lundberg JM, Cao Y, et al. The TGF-β superfamily as potential therapeutic targets in pancreatic cancer. Front Oncol, 2024, 14: 1362247. doi: 10.3389/fonc.2024.1362247.
42.	di Miceli N, Baioni C, Barbieri L, et al. TGF-β signaling loop in pancreatic ductal adenocarcinoma activates fibroblasts and increases tumor cell aggressiveness. Cancers (Basel), 2024, 16(21): 3705. doi: 10.3390/cancers16213705.
43.	Glapiński F, Zaj?c W, Fudalej M, et al. The role of the tumor microenvironment in pancreatic ductal adenocarcinoma: recent advancements and emerging therapeutic strategies. Cancers (Basel), 2025, 17(10): 1599. doi: 10.3390/cancers17101599.
44.	Grant G, Ferrer CM. The role of the immune tumor microenvironment in shaping metastatic dissemination, dormancy, and outgrowth. Trends Cell Biol, 2025, S0962-8924(25)00124-2. doi: 10.1016/j.tcb.2025.05.006.
45.	Liang Y, Chen WM, Zhang Y, et al. Remodeling the tumor dormancy ecosystem to prevent recurrence and metastasis. Signal Transduct Target Ther, 2026, 11(1): 1. doi: 10.1038/s41392-025-02328-2.
46.	Arsenijevic T, Coulonval K, Raspé E, et al. CDK4/6 inhibitors in pancreatobiliary cancers: opportunities and challenges. Cancers (Basel), 2023, 15(3): 968. doi: 10.3390/cancers15030968.
47.	Zhao S, Zhang H, Yang N, et al. A narrative review about CDK4/6 inhibitors in the setting of drug resistance: updates on biomarkers and therapeutic strategies in breast cancer. Transl Cancer Res, 2023, 12(6): 1617-1634.
48.	Chiorean EG, Picozzi V, Li CP, et al. Efficacy and safety of abemaciclib alone and with PI3K/mTOR inhibitor LY3023414 or galunisertib versus chemotherapy in previously treated metastatic pancreatic adenocarcinoma: a randomized controlled trial. Cancer Med, 2023, 12(20): 20353-20364.
49.	Kumarasamy V, Ruiz A, Nambiar R, et al. Chemotherapy impacts on the cellular response to CDK4/6 inhibition: distinct mechanisms of interaction and efficacy in models of pancreatic cancer. Oncogene, 2020, 39(9): 1831-1845.
50.	Hidalgo M, Garcia-Carbonero R, Lim KH, et al. A preclinical and phase Ⅰb study of palbociclib plus Nab-Paclitaxel in patients with metastatic adenocarcinoma of the pancreas. Cancer Res Commun, 2022, 2(11): 1326-1333.
51.	Franco J, Witkiewicz AK, Knudsen ES. CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget, 2014, 5(15): 6512-6525.
52.	Liu J, Zhang B, Huang B, et al. A stumbling block in pancreatic cancer treatment: drug resistance signaling networks. Front Cell Dev Biol, 2025, 12: 1462808. doi: 10.3389/fcell.2024.1462808.
53.	Liu F, Korc M. Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther, 2012, 11(10): 2138-2148.
54.	Qian J, Liao G, Chen M, et al. Advancing cancer therapy: new frontiers in targeting DNA damage response. Front Pharmacol, 2024, 15: 1474337. doi: 10.3389/fphar.2024.1474337.
55.	Prevo R, Fokas E, Reaper PM, et al. The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol Ther, 2012, 13(11): 1072-1081.
56.	Morimoto Y, Takada K, Takeuchi O, et al. Prexasertib increases the sensitivity of pancreatic cancer cells to gemcitabine and S-1. Oncol Rep, 2020, 43(2): 689-699.
57.	Cuneo KC, Morgan MA, Sahai V, et al. Dose escalation trial of the Wee1 inhibitor adavosertib (AZD1775) in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer. J Clin Oncol, 2019, 37(29): 2643-2650.
58.	Wang W, Zhao R, Wang Y, et al. PLK1 in cancer therapy: a comprehensive review of immunomodulatory mechanisms and therapeutic opportunities. Front Immunol, 2025, 16: 1602752. doi: 10.3389/fimmu.2025.1602752.
59.	Vats P, Saini C, Baweja B, et al. Aurora kinases signaling in cancer: from molecular perception to targeted therapies. Cancer, 2025, 24(1): 180. doi: 10.1186/s12943-025-02353-3.
60.	Russano F, Sturlese M, Dall’Olmo L, et al. MDM2 in tumor biology and cancer therapy: a review of current clinical trials. Int J Mol Sci, 2025, 27(1): 99. doi: 10.3390/ijms27010099.
61.	Knudsen ES, Witkiewicz AK, Sanidas I, et al. Targeting CDK2 for cancer therapy. Cell Rep, 2025, 44(8): 116140. doi: 10.1016/j.celrep.2025.116140.
62.	Liu D, Lu J, Chen C, et al. Mesothelin-associated anti-senescence through P53 in pancreatic ductal adenocarcinoma. Cancers (Basel), 2025, 17(12): 2058. doi: 10.3390/cancers17122058.
63.	Anichini G, Raggi C, Pastore M, et al. Combined inhibition of smoothened and the DNA damage checkpoint WEE1 exerts antitumor activity in cholangiocarcinoma. Mol Cancer Ther, 2023, 22(3): 343-356.

1. Mannucci A, Goel A. Advances in pancreatic cancer early diagnosis, prevention, and treatment: the past, the present, and the future. CA Cancer J Clin, 2026, 76(1): e70035. doi: 10.3322/caac.70035.
2. Stoop TF, Javed AA, Oba A, et al. Pancreatic cancer. Lancet, 2025, 405(10485): 1182-1202.
3. Engeland K. Cell cycle regulation: p53-p21-RB signaling. Cell Death Differ, 2022, 29(5): 946-960.
4. Lee JJ, Yeh JJ. Updates in molecular profiling of pancreatic ductal adenocarcinoma. Surg Clin North Am, 2024, 104(5): 939-950.
5. Stefanoudakis D, Frountzas M, Schizas D, et al. Significance of TP53, CDKN2A, SMAD4 and KRAS in pancreatic cancer. Curr Issues Mol Biol, 2024, 46(4): 2827-2844.
6. Jazieh K, Tsai J, Solomon S, et al. Identification of candidate alterations mediating KRASG12C inhibitor resistance in advanced colorectal and pancreatic cancers. Clin Cancer Res, 2025, 31(5): 899-906.
7. Tiede KOM, Teixeira MF, Moura M, et al. Efficacy and safety signals from early-phase studies of KRAS inhibition in pancreatic cancer. Sci Rep, 2026, 16(1): 13189. doi: 10.1038/s41598-026-40757-3.
8. Mercadante AA, Kasi A. Genetics, cancer cell cycle phases. Treasure Island (FL).: StatPearls Publishing, 2026. https://www.ncbi.nlm.nih.gov/books/NBK563158/.
9. Pellarin I, Dall’Acqua A, Favero A, et al. Cyclin-dependent protein kinases and cell cycle regulation in biology and disease. Signal Transduct Target Ther, 2025, 10(1): 11. doi: 10.1038/s41392-024-02080-z.
10. Shalaby A, Sadri N, Xue Y. Molecular pathology of pancreatic ductal adenocarcinoma. Cancers (Basel), 2025, 17(21): 3549. doi: 10.3390/cancers17213549.
11. Rozengurt E, Eibl G. Pancreatic cancer: molecular pathogenesis and emerging therapeutic strategies. Signal Transduct Target Ther, 2026, 11(1): 6. doi: 10.1038/s41392-025-02499-y.
12. Linehan A, O’Reilly M, McDermott R, et al. Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies. Front Med (Lausanne), 2024, 11: 1369136. doi: 10.3389/fmed.2024.1369136.
13. Casacuberta-Serra S, González-Larreategui í, Capitán-Leo D, et al. MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer. Signal Transduct Target Ther, 2024, 9(1): 205. doi: 10.1038/s41392-024-01907-z.
14. Palanivel C, Madduri LSV, Hein AL, et al. PR55α-controlled protein phosphatase 2A inhibits p16 expression and blocks cellular senescence induction by γ-irradiation. Aging (Albany NY), 2024, 16(5): 4116-4137.
15. Yakar D?, Bozk?rl? BO, Ceyhan GO. Genetic landscape of pancreatic cancer: a narrative review. Chin Clin Oncol, 2022, 11(1): 5. doi: 10.21037/cco-22-4.
16. Rahnamay Farnood P, Danesh Pazhooh R, Asemi Z, et al. DNA damage response and repair in pancreatic cancer development and therapy. DNA Repair (Amst), 2021, 103: 103116. doi: 10.1016/j.dnarep.2021.103116.
17. Tsanov KM, Barriga FM, Ho YJ, et al. SMAD4 induces opposite effects on metastatic growth from pancreatic tumors depending on the organ of residence. Nat Cancer, 2025, 6(11): 1839-1856.
18. Baba AB, Rah B, Bhat GR, et al. Transforming growth factor-beta (TGF-β) signaling in cancer-a betrayal within. Front Pharmacol, 2022, 13: 791272. doi: 10.3389/fphar.2022.791272.
19. Dreyer SB, Upstill-Goddard R, Paulus-Hock V, et al. Targeting DNA damage response and replication stress in pancreatic cancer. Gastroenterology, 2021, 160(1): 362-377.
20. Kumar NA, Manasa P, Chandrasekaran J. Revisiting CHK1 and WEE1 kinases as therapeutic targets in cancer. Biochim Biophys Acta Rev Cancer, 2025, 1880(6): 189482. doi: 10.1016/j.bbcan.2025.189482.
21. Kciuk M, Wanke K, Marciniak B, et al. Targeting ATR-CHK1 and ATM-CHK2 axes in pancreatic cancer-a comprehensive review of literature. Int J Mol Sci, 2026, 27(3): 1152. doi: 10.3390/ijms27031152.
22. Hayashi H, Uemura N, Zhao L, et al. Biological significance of YAP/TAZ in pancreatic ductal adenocarcinoma. Front Oncol, 2021, 11: 700315. doi: 10.3389/fonc.2021.700315.
23. Hartupee C, Nagalo BM, Chabu CY, et al. Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target. Front Immunol, 2024, 15: 1287459. doi: 10.3389/fimmu.2024.1287459.
24. Zhu Q, Wei X, Qu Z, et al. The roles of cell cycle proteins in regulating the tumor immune microenvironment. Genes Dis, 2025, 13(1): 101706. doi: 10.1016/j.gendis.2025.101706.
25. Maleki EH, Bahrami AR, Matin MM. Cancer cell cycle heterogeneity as a critical determinant of therapeutic resistance. Genes Dis, 2023, 11(1): 189-204.
26. Liu YP, Zheng CC, Huang YN, et al. Molecular mechanisms of chemo- and radiotherapy resistance and the potential implications for cancer treatment. MedComm (2020), 2021, 2(3): 315-340.
27. Sigirli S, Karakas D. Fibrotic fortresses and therapeutic frontiers: pancreatic stellate cells and the extracellular matrix in pancreatic cancer. Cancer Med, 2025, 14(11): e70788. doi: 10.1002/cam4.70788.
28. Sherman MH, Beatty GL. Tumor microenvironment in pancreatic cancer pathogenesis and therapeutic resistance. Annu Rev Pathol, 2023, 18: 123-148.
29. Zhang J, Wang Y, Wang L, et al. Pancreatic ductal adenocarcinoma chemoresistance: from metabolism reprogramming to novel treatment. Chin Med J (Engl), 2024, 137(4): 408-420.
30. Kpeglo D, Haddrick M, Knowles MA, et al. Modelling and breaking down the biophysical barriers to drug delivery in pancreatic cancer. Lab Chip, 2024, 24(4): 854-868.
31. Liu C, Li C, Liu Y. The role of metabolic reprogramming in pancreatic cancer chemoresistance. Front Pharmacol, 2023, 13: 1108776. doi: 10.3389/fphar.2022.1108776.
32. Dalin S, Sullivan MR, Lau AN, et al. Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance. Cancer Res, 2019, 79(22): 5723-5733.
33. Qin Q, Yu R, Eriksson JE, et al. Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma therapy: challenges and opportunities. Cancer Lett, 2024, 591: 216859. doi: 10.1016/j.canlet.2024.216859.
34. Zhang H, Cao K, Xiang J, et al. Hypoxia induces immunosuppression, metastasis and drug resistance in pancreatic cancers. Cancer Lett, 2023, 571: 216345. doi: 10.1016/j.canlet.2023.216345.
35. Ju Y, Xu D, Liao MM, et al. Barriers and opportunities in pancreatic cancer immunotherapy. NPJ Precis Oncol, 2024, 8(1): 199. doi: 10.1038/s41698-024-00681-z.
36. Matsumoto R, Tanoue K, Nakayama C, et al. Strategies to target the tumor-associated macrophages in the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma. Cancers (Basel), 2025, 17(18): 3090. doi: 10.3390/cancers17183090.
37. Joseph AM, Al Aiyan A, Al-Ramadi B, et al. Innate and adaptive immune-directed tumour microenvironment in pancreatic ductal adenocarcinoma. Front Immunol, 2024, 15: 1323198. doi: 10.3389/fimmu.2024.1323198.
38. Fahey CG, Cordova AF, Gedeon PC, et al. Targeting STING to generate therapeutic anti-tumor immunity. Cancer Cell, 2026, 44(2): 260-280.
39. Costamagna A, Ghiglione N, Martini M. The molecular logic of early metastasis in pancreatic cancer: crosstalk between tumor and microenvironment. Front Cell Dev Biol, 2025, 13: 1726581. doi: 10.3389/fcell.2025.1726581.
40. Maddipati R. Metastatic heterogeneity in pancreatic cancer: mechanisms and opportunities for targeted intervention. J Clin Invest, 2025, 135(14): e191943. doi: 10.1172/JCI191943.
41. Tindall RR, Bailey-Lundberg JM, Cao Y, et al. The TGF-β superfamily as potential therapeutic targets in pancreatic cancer. Front Oncol, 2024, 14: 1362247. doi: 10.3389/fonc.2024.1362247.
42. di Miceli N, Baioni C, Barbieri L, et al. TGF-β signaling loop in pancreatic ductal adenocarcinoma activates fibroblasts and increases tumor cell aggressiveness. Cancers (Basel), 2024, 16(21): 3705. doi: 10.3390/cancers16213705.
43. Glapiński F, Zaj?c W, Fudalej M, et al. The role of the tumor microenvironment in pancreatic ductal adenocarcinoma: recent advancements and emerging therapeutic strategies. Cancers (Basel), 2025, 17(10): 1599. doi: 10.3390/cancers17101599.
44. Grant G, Ferrer CM. The role of the immune tumor microenvironment in shaping metastatic dissemination, dormancy, and outgrowth. Trends Cell Biol, 2025, S0962-8924(25)00124-2. doi: 10.1016/j.tcb.2025.05.006.
45. Liang Y, Chen WM, Zhang Y, et al. Remodeling the tumor dormancy ecosystem to prevent recurrence and metastasis. Signal Transduct Target Ther, 2026, 11(1): 1. doi: 10.1038/s41392-025-02328-2.
46. Arsenijevic T, Coulonval K, Raspé E, et al. CDK4/6 inhibitors in pancreatobiliary cancers: opportunities and challenges. Cancers (Basel), 2023, 15(3): 968. doi: 10.3390/cancers15030968.
47. Zhao S, Zhang H, Yang N, et al. A narrative review about CDK4/6 inhibitors in the setting of drug resistance: updates on biomarkers and therapeutic strategies in breast cancer. Transl Cancer Res, 2023, 12(6): 1617-1634.
48. Chiorean EG, Picozzi V, Li CP, et al. Efficacy and safety of abemaciclib alone and with PI3K/mTOR inhibitor LY3023414 or galunisertib versus chemotherapy in previously treated metastatic pancreatic adenocarcinoma: a randomized controlled trial. Cancer Med, 2023, 12(20): 20353-20364.
49. Kumarasamy V, Ruiz A, Nambiar R, et al. Chemotherapy impacts on the cellular response to CDK4/6 inhibition: distinct mechanisms of interaction and efficacy in models of pancreatic cancer. Oncogene, 2020, 39(9): 1831-1845.
50. Hidalgo M, Garcia-Carbonero R, Lim KH, et al. A preclinical and phase Ⅰb study of palbociclib plus Nab-Paclitaxel in patients with metastatic adenocarcinoma of the pancreas. Cancer Res Commun, 2022, 2(11): 1326-1333.
51. Franco J, Witkiewicz AK, Knudsen ES. CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget, 2014, 5(15): 6512-6525.
52. Liu J, Zhang B, Huang B, et al. A stumbling block in pancreatic cancer treatment: drug resistance signaling networks. Front Cell Dev Biol, 2025, 12: 1462808. doi: 10.3389/fcell.2024.1462808.
53. Liu F, Korc M. Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther, 2012, 11(10): 2138-2148.
54. Qian J, Liao G, Chen M, et al. Advancing cancer therapy: new frontiers in targeting DNA damage response. Front Pharmacol, 2024, 15: 1474337. doi: 10.3389/fphar.2024.1474337.
55. Prevo R, Fokas E, Reaper PM, et al. The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol Ther, 2012, 13(11): 1072-1081.
56. Morimoto Y, Takada K, Takeuchi O, et al. Prexasertib increases the sensitivity of pancreatic cancer cells to gemcitabine and S-1. Oncol Rep, 2020, 43(2): 689-699.
57. Cuneo KC, Morgan MA, Sahai V, et al. Dose escalation trial of the Wee1 inhibitor adavosertib (AZD1775) in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer. J Clin Oncol, 2019, 37(29): 2643-2650.
58. Wang W, Zhao R, Wang Y, et al. PLK1 in cancer therapy: a comprehensive review of immunomodulatory mechanisms and therapeutic opportunities. Front Immunol, 2025, 16: 1602752. doi: 10.3389/fimmu.2025.1602752.
59. Vats P, Saini C, Baweja B, et al. Aurora kinases signaling in cancer: from molecular perception to targeted therapies. Cancer, 2025, 24(1): 180. doi: 10.1186/s12943-025-02353-3.
60. Russano F, Sturlese M, Dall’Olmo L, et al. MDM2 in tumor biology and cancer therapy: a review of current clinical trials. Int J Mol Sci, 2025, 27(1): 99. doi: 10.3390/ijms27010099.
61. Knudsen ES, Witkiewicz AK, Sanidas I, et al. Targeting CDK2 for cancer therapy. Cell Rep, 2025, 44(8): 116140. doi: 10.1016/j.celrep.2025.116140.
62. Liu D, Lu J, Chen C, et al. Mesothelin-associated anti-senescence through P53 in pancreatic ductal adenocarcinoma. Cancers (Basel), 2025, 17(12): 2058. doi: 10.3390/cancers17122058.
63. Anichini G, Raggi C, Pastore M, et al. Combined inhibition of smoothened and the DNA damage checkpoint WEE1 exerts antitumor activity in cholangiocarcinoma. Mol Cancer Ther, 2023, 22(3): 343-356.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research advances in the role of cell cycle dysregulation in the development and progression of pancreatic ductal adenocarcinoma

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