Research progress of molecular targeted therapy for pancreatic cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HE Ru ¹ , DONG Shi ² ,  ZHOU Wence ^1,3

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

Corresponding author：

ZHOU Wence, Email: zhouwc129@163.com

Keywords：

pancreatic cancer; genome; molecular target; targeted therapy

DOI：

10.7507/1007-9424.202205071

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the progress in related basic research of molecular targeted therapy in pancreatic cancer. Method The relevant literatures on oncogenes, epigenome, tumour microenvironment and immunotherapy in recent years at home and abroad were reviewed. Results In basic research, molecularly targeted drugs had shown some efficacy in the treatment of progression of pancreatic cancer, however, in clinical trials, more satisfactory results were not achieved. Conclusion Molecularly targeted therapies for pancreatic cancer are still at a preliminary stage of exploration, and basic research has not yet been effectively translated clinically, which requires further exploration efforts in subsequent studies to provide a more solid and reliable basis for precise treatment of pancreatic cancer and achieve better clinical benefits.

Citation： HE Ru, DONG Shi, ZHOU Wence. Research progress of molecular targeted therapy for pancreatic cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(11): 1534-1540. doi: 10.7507/1007-9424.202205071 Copy

1.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2.	Elsayed M, Abdelrahim M. The latest advancement in pancreatic ductal adenocarcinoma therapy: a review article for the latest guidelines and novel therapies. Biomedicines, 2021, 9(4): 389. doi: 10.3390/biomedicines9040389.
3.	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin, 2019, 69(1): 7-34.
4.	GLOBOCAN. Cancer today. https://gco.iarc.fr/today/home.
5.	Chamma H, Vila IK, Taffoni C, et al. Activation of STING in the pancreatic tumor microenvironment: A novel therapeutic opportunity. Cancer Lett, 2022, 538: 215694. doi: 10.1016/j.canlet.2022.215694.
6.	Huang X, Zhang G, Liang T. Subtyping for pancreatic cancer precision therapy. Trends Pharmacol Sci, 2022, 43(6): 482-494.
7.	Traub B, Link KH, Kornmann M. Curing pancreatic cancer. Semin Cancer Biol, 2021, 76: 232-246.
8.	Grapa CM, Mocan T, Gonciar D, et al. Epidermal growth factor receptor and its role in pancreatic cancer treatment mediated by nanoparticles. Int J Nanomedicine, 2019, 14: 9693-9706.
9.	Nedaeinia R, Avan A, Manian M, et al. EGFR as a potential target for the treatment of pancreatic cancer: dilemma and controversies. Curr Drug Targets, 2014, 15(14): 1293-1301.
10.	Blasco MT, Navas C, Martín-Serrano G, et al. Complete regression of advanced pancreatic ductal adenocarcinomas upon combined inhibition of EGFR and C-RAF. Cancer Cell, 2019, 35(4): 573-587.
11.	Mohammed A, Janakiram NB, Li Q, et al. The epidermal growth factor receptor inhibitor gefitinib prevents the progression of pancreatic lesions to carcinoma in a conditional LSL-Kras^G12D/+ transgenic mouse model. Cancer Prev Res (Phila), 2010, 3(11): 1417-1426.
12.	Huguet F, Fernet M, Giocanti N, et al. Afatinib, an irreversible EGFR family inhibitor, shows activity toward pancreatic cancer cells, alone and in combination with radiotherapy, independent of KRAS status. Target Oncol, 2016, 11(3): 371-381.
13.	Momeny M, Esmaeili F, Hamzehlou S, et al. The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells. Cell Oncol (Dordr), 2019, 42(4): 491-504.
14.	Roskoski R. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res, 2014, 79: 34-74.
15.	Brunetti O, Badalamenti G, De Summa S, et al. Molecular characterization of a long-term survivor double metastatic non-small cell lung cancer and pancreatic ductal adenocarcinoma treated with gefitinib in combination with gemcitabine plus Nab-paclitaxel and mFOLFOX6 as first and second line therapy. Cancers (Basel), 2019, 11(6): 749. doi: 10.3390/cancers11060749.
16.	Haas M, Waldschmidt DT, Stahl M, et al. Afatinib plus gemcitabine versus gemcitabine alone as first-line treatment of metastatic pancreatic cancer: The randomised, open-label phase Ⅱ ACCEPT study of the Arbeitsgemeinschaft Internistische Onkologie with an integrated analysis of the ‘burden of therapy’ method. Eur J Cancer, 2021, 146: 95-106.
17.	van Geel RMJM, van Brummelen EMJ, Eskens FALM, et al. Phase 1 study of the pan-HER inhibitor dacomitinib plus the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutation-positive colorectal, non-small-cell lung and pancreatic cancer. Br J Cancer, 2020, 122(8): 1166-1174.
18.	Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. Semin Cancer Biol, 2019, 59: 125-132.
19.	Arafeh R, Samuels Y. PIK3CA in cancer: The past 30 years. Semin Cancer Biol, 2019, 59: 36-49.
20.	Hayes TK, Neel NF, Hu C, et al. Long-term ERK inhibition in KRAS-mutant pancreatic cancer is associated with MYC degradation and senescence-like growth suppression. Cancer Cell, 2016, 29(1): 75-89.
21.	Soares HP, Ming M, Mellon M, et al. Dual PI3K/mTOR inhibitors induce rapid overactivation of the MEK/ERK pathway in human pancreatic cancer cells through suppression of mTORC2. Mol Cancer Ther, 2015, 14(4): 1014-1023.
22.	Walter K, Tiwary K, Trajkovic-Arsic M, et al. MEK inhibition targets cancer stem cells and impedes migration of pancreatic cancer cells in vitro and in vivo. Stem Cells Int, 2019, 2019: 8475389. doi: 10.1155/2019/8475389.
23.	Kastenhuber ER, Lowe SW. Putting p53 in context. Cell, 2017, 170(6): 1062-1078.
24.	Donehower LA, Soussi T, Korkut A, et al. Integrated analysis of TP53 gene and pathway alterations in the cancer genome atlas. Cell Rep, 2019, 28(5): 1370-1384.
25.	Fiorini C, Menegazzi M, Padroni C, et al. Autophagy induced by p53-reactivating molecules protects pancreatic cancer cells from apoptosis. Apoptosis, 2013, 18(3): 337-346.
26.	Rangel LP, Ferretti GDS, Costa CL, et al. p53 reactivation with induction of massive apoptosis-1 (PRIMA-1) inhibits amyloid aggregation of mutant p53 in cancer cells. J Biol Chem, 2019, 294(10): 3670-3682.
27.	Liu X, Zhang L, Thu PM, et al. Sodium cantharidinate, a novel anti-pancreatic cancer agent that activates functional p53. Sci China Life Sci, 2021, 64(8): 1295-1310.
28.	McCubrey JA, Meher AK, Akula SM, et al. Wild type and gain of function mutant TP53 can regulate the sensitivity of pancreatic cancer cells to chemotherapeutic drugs, EGFR/Ras/Raf/MEK, and PI3K/mTORC1/GSK-3 pathway inhibitors, nutraceuticals and alter metabolic properties. Aging (Albany NY), 2022, 14(8): 3365-3386.
29.	Beaver JA, Amiri-Kordestani L, Charlab R, et al. FDA approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res, 2015, 21(21): 4760-4766.
30.	Chou A, Froio D, Nagrial AM, et al. Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. Gut, 2018, 67(12): 2142-2155.
31.	Willobee BA, Gaidarski AA, Dosch AR, et al. Combined blockade of MEK and CDK4/6 pathways induces senescence to improve survival in pancreatic ductal adenocarcinoma. Mol Cancer Ther, 2021, 20(7): 1246-1256.
32.	Al Baghdadi T, Halabi S, Garrett-Mayer E, et al. Palbociclib in patients with pancreatic and biliary cancer with CDKN2A alterations: Results from the targeted agent and profiling utilization registry study. JCO Precis Oncol, 2019, 3: 1-8.
33.	Gough NR, Xiang X, Mishra L. TGF-β signaling in liver, pancreas, and gastrointestinal diseases and cancer. Gastroenterology, 2021, 161(2): 434-452.
34.	Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21. 1. Science, 1996, 271(5247): 350-353.
35.	Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell, 2003, 113(6): 685-700.
36.	Rana M, Kansal R, Chaib M, et al. The pancreatic cancer immune tumor microenvironment is negatively remodeled by gemcitabine while TGF-β receptor plus dual checkpoint inhibition maintains antitumor immune cells. Mol Carcinog, 2022, 61(6): 549-557.
37.	Zhao X, Yang X, Wang X, et al. Penetration cascade of size switchable nanosystem in desmoplastic stroma for improved pancreatic cancer therapy. ACS Nano, 2021, 15(9): 14149-14161.
38.	Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet, 2016, 387(10018): 545-557.
39.	Hong E, Park S, Ooshima A, et al. Inhibition of TGF-β signalling in combination with nal-IRI plus 5-Fluorouracil/Leucovorin suppresses invasion and prolongs survival in pancreatic tumour mouse models. Sci Rep, 2020, 10(1): 2935. doi: 10.1038/s41598-020-59893-5.
40.	Forster T, Huettner FJ, Springfeld C, et al. Cetuximab in pancreatic cancer therapy: a systematic review and meta-analysis. Oncology, 2020, 98(1): 53-60.
41.	Sun Q, Zhang B, Hu Q, et al. The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer. Theranostics, 2018, 8(18): 5072-5087.
42.	Haq F, Sung YN, Park I, et al. FGFR1 expression defines clinically distinct subtypes in pancreatic cancer. J Transl Med, 2018, 16(1): 374. doi: 10.1186/s12967-018-1743-9.
43.	Zhang H, Hylander BL, LeVea C, et al. Enhanced FGFR signalling predisposes pancreatic cancer to the effect of a potent FGFR inhibitor in preclinical models. Br J Cancer, 2014, 110(2): 320-329.
44.	Lin Q, Qian Z, Jusko WJ, et al. Synergistic pharmacodynamic effects of gemcitabine and fibroblast growth factor receptor inhibitors on pancreatic cancer cell cycle kinetics and proliferation. J Pharmacol Exp Ther, 2021, 377(3): 370-384.
45.	Yang Z, Liang SQ, Saliakoura M, et al. Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS-mutant cancer. EMBO Mol Med, 2021, 13(9): e13193. doi: 10.15252/emmm.202013193.
46.	LaFave LM, Kartha VK, Ma S, et al. Epigenomic state transitions characterize tumor progression in mouse lung adenocarcinoma. Cancer Cell, 2020, 38(2): 212-228.
47.	Khan AA, Liu X, Yan X, et al. An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression. Cancer Metastasis Rev, 2021, 40(1): 245-272.
48.	Thompson JK, Bednar F. Clinical utility of epigenetic changes in pancreatic adenocarcinoma. Epigenomes, 2021, 5(4): 20. doi: 10.3390/epigenomes5040020.
49.	Wang SS, Xu J, Ji KY, et al. Epigenetic alterations in pancreatic cancer metastasis. Biomolecules, 2021, 11(8): 1082. doi: 10.3390/biom11081082.
50.	Krebs AM, Mitschke J, Lasierra Losada M, et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol, 2017, 19(5): 518-529.
51.	Wong KK. DNMT1 as a therapeutic target in pancreatic cancer: mechanisms and clinical implications. Cell Oncol (Dordr), 2020, 43(5): 779-792.
52.	Booth L, Poklepovic A, Dent P. Neratinib decreases pro-survival responses of [sorafenib + vorinostat] in pancreatic cancer. Biochem Pharmacol, 2020, 178: 114067. doi: 10.1016/j.bcp.2020.114067.
53.	Carpenter ES, Steele NG, Pasca di Magliano M. Targeting the microenvironment to overcome gemcitabine resistance in pancreatic cancer. Cancer Res, 2020, 80(15): 3070-3071.
54.	Qin S, Li Q, Gu S, et al. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol, 2021, 6(7): 559-568.
55.	Pysz MA, Machtaler SB, Seeley ES, et al. Vascular endothelial growth factor receptor type 2-targeted contrast-enhanced US of pancreatic cancer neovasculature in a genetically engineered mouse model: potential for earlier detection. Radiology, 2015, 274(3): 790-799.
56.	Torphy RJ, Zhu Y, Schulick RD. Immunotherapy for pancreatic cancer: Barriers and breakthroughs. Ann Gastroenterol Surg, 2018, 2(4): 274-281.
57.	Chen IM, Johansen JS, Theile S, et al. Randomized phase Ⅱ study of nivolumab with or without ipilimumab combined with stereotactic body radiotherapy for refractory metastatic pancreatic cancer (CheckPAC). J Clin Oncol, 2022, 40(27): 3180-3189.
58.	Fumet JD, Limagne E, Thibaudin M, et al. Precision medicine phase Ⅱ study evaluating the efficacy of a double immunotherapy by durvalumab and tremelimumab combined with olaparib in patients with solid cancers and carriers of homologous recombination repair genes mutation in response or stable after olaparib treatment. BMC Cancer, 2020, 20(1): 748. doi: 10.1186/s12885-020-07253-x.
59.	Staudt RE, Carlson RD, Snook AE. Targeting gastrointestinal cancers with chimeric antigen receptor (CAR)-T cell therapy. Cancer Biol Ther, 2022, 23(1): 127-133.
60.	Kumai T, Mizukoshi E, Hashiba T, et al. Effect of adoptive T-cell immunotherapy on immunological parameters and prognosis in patients with advanced pancreatic cancer. Cytotherapy, 2021, 23(2): 137-145.
61.	Raj D, Yang MH, Rodgers D, et al. Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma. Gut, 2019, 68(6): 1052-1064.
62.	Yuan LQ, Wang C, Lu DF, et al. Induction of apoptosis and ferroptosis by a tumor suppressing magnetic field through ROS-mediated DNA damage. Aging (Albany NY), 2020, 12(4): 3662-3681.

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2. Elsayed M, Abdelrahim M. The latest advancement in pancreatic ductal adenocarcinoma therapy: a review article for the latest guidelines and novel therapies. Biomedicines, 2021, 9(4): 389. doi: 10.3390/biomedicines9040389.
3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin, 2019, 69(1): 7-34.
4. GLOBOCAN. Cancer today. https://gco.iarc.fr/today/home.
5. Chamma H, Vila IK, Taffoni C, et al. Activation of STING in the pancreatic tumor microenvironment: A novel therapeutic opportunity. Cancer Lett, 2022, 538: 215694. doi: 10.1016/j.canlet.2022.215694.
6. Huang X, Zhang G, Liang T. Subtyping for pancreatic cancer precision therapy. Trends Pharmacol Sci, 2022, 43(6): 482-494.
7. Traub B, Link KH, Kornmann M. Curing pancreatic cancer. Semin Cancer Biol, 2021, 76: 232-246.
8. Grapa CM, Mocan T, Gonciar D, et al. Epidermal growth factor receptor and its role in pancreatic cancer treatment mediated by nanoparticles. Int J Nanomedicine, 2019, 14: 9693-9706.
9. Nedaeinia R, Avan A, Manian M, et al. EGFR as a potential target for the treatment of pancreatic cancer: dilemma and controversies. Curr Drug Targets, 2014, 15(14): 1293-1301.
10. Blasco MT, Navas C, Martín-Serrano G, et al. Complete regression of advanced pancreatic ductal adenocarcinomas upon combined inhibition of EGFR and C-RAF. Cancer Cell, 2019, 35(4): 573-587.
11. Mohammed A, Janakiram NB, Li Q, et al. The epidermal growth factor receptor inhibitor gefitinib prevents the progression of pancreatic lesions to carcinoma in a conditional LSL-Kras^G12D/+ transgenic mouse model. Cancer Prev Res (Phila), 2010, 3(11): 1417-1426.
12. Huguet F, Fernet M, Giocanti N, et al. Afatinib, an irreversible EGFR family inhibitor, shows activity toward pancreatic cancer cells, alone and in combination with radiotherapy, independent of KRAS status. Target Oncol, 2016, 11(3): 371-381.
13. Momeny M, Esmaeili F, Hamzehlou S, et al. The ERBB receptor inhibitor dacomitinib suppresses proliferation and invasion of pancreatic ductal adenocarcinoma cells. Cell Oncol (Dordr), 2019, 42(4): 491-504.
14. Roskoski R. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res, 2014, 79: 34-74.
15. Brunetti O, Badalamenti G, De Summa S, et al. Molecular characterization of a long-term survivor double metastatic non-small cell lung cancer and pancreatic ductal adenocarcinoma treated with gefitinib in combination with gemcitabine plus Nab-paclitaxel and mFOLFOX6 as first and second line therapy. Cancers (Basel), 2019, 11(6): 749. doi: 10.3390/cancers11060749.
16. Haas M, Waldschmidt DT, Stahl M, et al. Afatinib plus gemcitabine versus gemcitabine alone as first-line treatment of metastatic pancreatic cancer: The randomised, open-label phase Ⅱ ACCEPT study of the Arbeitsgemeinschaft Internistische Onkologie with an integrated analysis of the ‘burden of therapy’ method. Eur J Cancer, 2021, 146: 95-106.
17. van Geel RMJM, van Brummelen EMJ, Eskens FALM, et al. Phase 1 study of the pan-HER inhibitor dacomitinib plus the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutation-positive colorectal, non-small-cell lung and pancreatic cancer. Br J Cancer, 2020, 122(8): 1166-1174.
18. Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. Semin Cancer Biol, 2019, 59: 125-132.
19. Arafeh R, Samuels Y. PIK3CA in cancer: The past 30 years. Semin Cancer Biol, 2019, 59: 36-49.
20. Hayes TK, Neel NF, Hu C, et al. Long-term ERK inhibition in KRAS-mutant pancreatic cancer is associated with MYC degradation and senescence-like growth suppression. Cancer Cell, 2016, 29(1): 75-89.
21. Soares HP, Ming M, Mellon M, et al. Dual PI3K/mTOR inhibitors induce rapid overactivation of the MEK/ERK pathway in human pancreatic cancer cells through suppression of mTORC2. Mol Cancer Ther, 2015, 14(4): 1014-1023.
22. Walter K, Tiwary K, Trajkovic-Arsic M, et al. MEK inhibition targets cancer stem cells and impedes migration of pancreatic cancer cells in vitro and in vivo. Stem Cells Int, 2019, 2019: 8475389. doi: 10.1155/2019/8475389.
23. Kastenhuber ER, Lowe SW. Putting p53 in context. Cell, 2017, 170(6): 1062-1078.
24. Donehower LA, Soussi T, Korkut A, et al. Integrated analysis of TP53 gene and pathway alterations in the cancer genome atlas. Cell Rep, 2019, 28(5): 1370-1384.
25. Fiorini C, Menegazzi M, Padroni C, et al. Autophagy induced by p53-reactivating molecules protects pancreatic cancer cells from apoptosis. Apoptosis, 2013, 18(3): 337-346.
26. Rangel LP, Ferretti GDS, Costa CL, et al. p53 reactivation with induction of massive apoptosis-1 (PRIMA-1) inhibits amyloid aggregation of mutant p53 in cancer cells. J Biol Chem, 2019, 294(10): 3670-3682.
27. Liu X, Zhang L, Thu PM, et al. Sodium cantharidinate, a novel anti-pancreatic cancer agent that activates functional p53. Sci China Life Sci, 2021, 64(8): 1295-1310.
28. McCubrey JA, Meher AK, Akula SM, et al. Wild type and gain of function mutant TP53 can regulate the sensitivity of pancreatic cancer cells to chemotherapeutic drugs, EGFR/Ras/Raf/MEK, and PI3K/mTORC1/GSK-3 pathway inhibitors, nutraceuticals and alter metabolic properties. Aging (Albany NY), 2022, 14(8): 3365-3386.
29. Beaver JA, Amiri-Kordestani L, Charlab R, et al. FDA approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res, 2015, 21(21): 4760-4766.
30. Chou A, Froio D, Nagrial AM, et al. Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. Gut, 2018, 67(12): 2142-2155.
31. Willobee BA, Gaidarski AA, Dosch AR, et al. Combined blockade of MEK and CDK4/6 pathways induces senescence to improve survival in pancreatic ductal adenocarcinoma. Mol Cancer Ther, 2021, 20(7): 1246-1256.
32. Al Baghdadi T, Halabi S, Garrett-Mayer E, et al. Palbociclib in patients with pancreatic and biliary cancer with CDKN2A alterations: Results from the targeted agent and profiling utilization registry study. JCO Precis Oncol, 2019, 3: 1-8.
33. Gough NR, Xiang X, Mishra L. TGF-β signaling in liver, pancreas, and gastrointestinal diseases and cancer. Gastroenterology, 2021, 161(2): 434-452.
34. Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21. 1. Science, 1996, 271(5247): 350-353.
35. Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell, 2003, 113(6): 685-700.
36. Rana M, Kansal R, Chaib M, et al. The pancreatic cancer immune tumor microenvironment is negatively remodeled by gemcitabine while TGF-β receptor plus dual checkpoint inhibition maintains antitumor immune cells. Mol Carcinog, 2022, 61(6): 549-557.
37. Zhao X, Yang X, Wang X, et al. Penetration cascade of size switchable nanosystem in desmoplastic stroma for improved pancreatic cancer therapy. ACS Nano, 2021, 15(9): 14149-14161.
38. Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet, 2016, 387(10018): 545-557.
39. Hong E, Park S, Ooshima A, et al. Inhibition of TGF-β signalling in combination with nal-IRI plus 5-Fluorouracil/Leucovorin suppresses invasion and prolongs survival in pancreatic tumour mouse models. Sci Rep, 2020, 10(1): 2935. doi: 10.1038/s41598-020-59893-5.
40. Forster T, Huettner FJ, Springfeld C, et al. Cetuximab in pancreatic cancer therapy: a systematic review and meta-analysis. Oncology, 2020, 98(1): 53-60.
41. Sun Q, Zhang B, Hu Q, et al. The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer. Theranostics, 2018, 8(18): 5072-5087.
42. Haq F, Sung YN, Park I, et al. FGFR1 expression defines clinically distinct subtypes in pancreatic cancer. J Transl Med, 2018, 16(1): 374. doi: 10.1186/s12967-018-1743-9.
43. Zhang H, Hylander BL, LeVea C, et al. Enhanced FGFR signalling predisposes pancreatic cancer to the effect of a potent FGFR inhibitor in preclinical models. Br J Cancer, 2014, 110(2): 320-329.
44. Lin Q, Qian Z, Jusko WJ, et al. Synergistic pharmacodynamic effects of gemcitabine and fibroblast growth factor receptor inhibitors on pancreatic cancer cell cycle kinetics and proliferation. J Pharmacol Exp Ther, 2021, 377(3): 370-384.
45. Yang Z, Liang SQ, Saliakoura M, et al. Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS-mutant cancer. EMBO Mol Med, 2021, 13(9): e13193. doi: 10.15252/emmm.202013193.
46. LaFave LM, Kartha VK, Ma S, et al. Epigenomic state transitions characterize tumor progression in mouse lung adenocarcinoma. Cancer Cell, 2020, 38(2): 212-228.
47. Khan AA, Liu X, Yan X, et al. An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression. Cancer Metastasis Rev, 2021, 40(1): 245-272.
48. Thompson JK, Bednar F. Clinical utility of epigenetic changes in pancreatic adenocarcinoma. Epigenomes, 2021, 5(4): 20. doi: 10.3390/epigenomes5040020.
49. Wang SS, Xu J, Ji KY, et al. Epigenetic alterations in pancreatic cancer metastasis. Biomolecules, 2021, 11(8): 1082. doi: 10.3390/biom11081082.
50. Krebs AM, Mitschke J, Lasierra Losada M, et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol, 2017, 19(5): 518-529.
51. Wong KK. DNMT1 as a therapeutic target in pancreatic cancer: mechanisms and clinical implications. Cell Oncol (Dordr), 2020, 43(5): 779-792.
52. Booth L, Poklepovic A, Dent P. Neratinib decreases pro-survival responses of [sorafenib + vorinostat] in pancreatic cancer. Biochem Pharmacol, 2020, 178: 114067. doi: 10.1016/j.bcp.2020.114067.
53. Carpenter ES, Steele NG, Pasca di Magliano M. Targeting the microenvironment to overcome gemcitabine resistance in pancreatic cancer. Cancer Res, 2020, 80(15): 3070-3071.
54. Qin S, Li Q, Gu S, et al. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol, 2021, 6(7): 559-568.
55. Pysz MA, Machtaler SB, Seeley ES, et al. Vascular endothelial growth factor receptor type 2-targeted contrast-enhanced US of pancreatic cancer neovasculature in a genetically engineered mouse model: potential for earlier detection. Radiology, 2015, 274(3): 790-799.
56. Torphy RJ, Zhu Y, Schulick RD. Immunotherapy for pancreatic cancer: Barriers and breakthroughs. Ann Gastroenterol Surg, 2018, 2(4): 274-281.
57. Chen IM, Johansen JS, Theile S, et al. Randomized phase Ⅱ study of nivolumab with or without ipilimumab combined with stereotactic body radiotherapy for refractory metastatic pancreatic cancer (CheckPAC). J Clin Oncol, 2022, 40(27): 3180-3189.
58. Fumet JD, Limagne E, Thibaudin M, et al. Precision medicine phase Ⅱ study evaluating the efficacy of a double immunotherapy by durvalumab and tremelimumab combined with olaparib in patients with solid cancers and carriers of homologous recombination repair genes mutation in response or stable after olaparib treatment. BMC Cancer, 2020, 20(1): 748. doi: 10.1186/s12885-020-07253-x.
59. Staudt RE, Carlson RD, Snook AE. Targeting gastrointestinal cancers with chimeric antigen receptor (CAR)-T cell therapy. Cancer Biol Ther, 2022, 23(1): 127-133.
60. Kumai T, Mizukoshi E, Hashiba T, et al. Effect of adoptive T-cell immunotherapy on immunological parameters and prognosis in patients with advanced pancreatic cancer. Cytotherapy, 2021, 23(2): 137-145.
61. Raj D, Yang MH, Rodgers D, et al. Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma. Gut, 2019, 68(6): 1052-1064.
62. Yuan LQ, Wang C, Lu DF, et al. Induction of apoptosis and ferroptosis by a tumor suppressing magnetic field through ROS-mediated DNA damage. Aging (Albany NY), 2020, 12(4): 3662-3681.

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