A maze symbolizing drug resistance in pancreatic cancer, with a path being cleared by PRMT3 inhibition.

Pancreatic Cancer Breakthrough: New Hope in Overcoming Chemoresistance

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Lena Kashyap in Health & Wellness October 2026 • 4 min read.

"Scientists identify a novel mechanism by which pancreatic cancer cells develop resistance to chemotherapy, paving the way for innovative treatment strategies."


Pancreatic cancer remains one of the deadliest forms of cancer, characterized by its aggressive nature and poor response to conventional treatments. Despite advancements in cancer therapy, the five-year survival rate for pancreatic cancer is less than 8%. Surgical resection, while potentially curative, is only an option for about 20% of patients due to the cancer's often advanced stage at diagnosis.

For patients with locally advanced or metastatic tumors, chemotherapy is the primary treatment approach. Gemcitabine (GEM) has been a standard first-line treatment since the late 1990s, initially showing promise in controlling tumor growth. However, many patients eventually develop resistance to gemcitabine, rendering the treatment ineffective and contributing to the cancer's grim prognosis.

Recent research has focused on understanding the mechanisms behind chemoresistance in pancreatic cancer. Epigenetic modifications, such as DNA methylation and histone modification, have emerged as significant factors. A groundbreaking study published in 'Cancers' reveals a novel mechanism involving protein arginine methyltransferase 3 (PRMT3), offering new hope for overcoming drug resistance and improving treatment outcomes.

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The Burden of Pancreatic Cancer

Pancreatic cancer is described as the fourth leading cause of cancer-related death in Western countries and is predicted to become the second leading cause by 2030. Approximately 90% of cases are pancreatic ductal adenocarcinoma (PDAC), and the 5-year survival rate remains below 10%. The tumor microenvironment and intrinsic cancer-cell resistance to chemotherapy allow malignant cells to survive treatment and complicate care.

Standard Treatment and Resistance

Limited treatment options and resistance to standard-of-care therapies contribute to PDAC's poor prognosis, with the disease predicted to become the second leading cause of cancer deaths by 2030. Chemoresistance is multifactorial and reflects interactions among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment. Researchers are investigating approaches in numerous Phase I-III clinical trials, while improved understanding of tumor heterogeneity may support better diagnosis, monitoring, and treatment selection.

Understanding Chemoresistance

Reviews identify the development of drug resistance as a principal reason current pancreatic cancer treatments lack efficacy. Research has increasingly emphasized the tumor microenvironment as an important contributor to chemoresistance. Resistance to gemcitabine is described as multifactorial, involving interplay among pancreatic cancer cells, the tumor microenvironment, and cancer stem cells.

Unlocking the Mystery of Chemoresistance: The Role of PRMT3

A maze symbolizing drug resistance in pancreatic cancer, with a path being cleared by PRMT3 inhibition.

The study, led by researchers at the National Institute of Cancer Research and Kaohsiung Medical University, investigated the role of PRMT3 in gemcitabine resistance. Previous research indicated that PRMT3, an epigenetic modifying enzyme, is dysregulated in gemcitabine-resistant pancreatic cancer cells. This new research aimed to elucidate how PRMT3 contributes to this resistance.

The researchers found that overexpression of PRMT3 led to increased resistance to gemcitabine in pancreatic cancer cells, while reducing PRMT3 restored sensitivity to the drug. This crucial finding highlights PRMT3 as a key player in the chemoresistance process. Further investigation identified ATP-binding cassette subfamily G member 2 (ABCG2) as a novel PRMT3 target. ABCG2 is a well-known contributor to drug resistance in various cancers.

  • PRMT3 Overexpression:Increases resistance to gemcitabine.
  • ABCG2 Identification:Identified as a novel PRMT3 target.
  • mRNA Stability:PRMT3 upregulates ABCG2 expression by increasing its mRNA stability.
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PRMT3 and Gemcitabine Resistance

Recent research reports that PRMT3 can enhance pancreatic cancer resistance to gemcitabine by methylating the RNA recognition motif of hnRNPA1. This modification promotes hnRNPA1 binding to ABCG2, increasing ABCG2 expression. The cited study, published in Cancers in 2018, specifically examined Protein Arginine Methyltransferase 3, hnRNPA1, ABCG2, and chemoresistance in pancreatic cancer.

Limits of the PRMT3 Finding

The reported experiment did not show gemcitabine resistance in every tested cell group. Only PRMT3-overexpressing cells were resistant to gemcitabine in the cited result. This limits the finding to the experimental PRMT3-overexpression context rather than establishing that all pancreatic cancer cells respond identically.

The study further revealed that PRMT3 upregulates ABCG2 expression by increasing its mRNA stability. This means that PRMT3 helps ABCG2 mRNA last longer, leading to increased production of the ABCG2 protein. ABCG2 functions as a drug efflux pump, actively removing gemcitabine from cancer cells and reducing its effectiveness. This mechanism directly contributes to the development of chemoresistance.

A Novel Target for Treatment

These findings provide a potential novel strategy for treating gemcitabine-resistant pancreatic cancer. By inhibiting PRMT3, researchers may be able to reduce ABCG2 expression and restore cancer cells' sensitivity to chemotherapy. This approach could significantly improve treatment outcomes for patients with this deadly disease.

How PRMT3 may help resistant cells withstand several drugs

The cell experiments suggest the effect was not limited to gemcitabine: PRMT3-overexpressing cells also resisted other tested chemotherapy drugs. That points to a possible multidrug-resistance role in this experimental setting, rather than a gemcitabine-only effect.[1]

Inhibiting PRMT3 reduced ABCG2 expression in both PRMT3-overexpressing cells and resistant PANC-1-R cells. The result links PRMT3 inhibition to a change in a resistance-associated gene, but does not itself show that inhibition restored drug sensitivity in those cells.[1]

The proposed chain connects PRMT3-mediated methylation of hnRNPA1 with stronger hnRNPA1 binding to ABCG2 and greater drug resistance. This offers a mechanism for the cell findings, rather than evidence that the same sequence determines treatment response in patients.[2]

Where the PRMT3 mechanism has boundaries

  • The reported gemcitabine resistance appeared in PRMT3-overexpressing cells, so the result does not establish that all tested cell groups become resistant.[1]
  • The ABCG2 mRNA response depended on the hnRNPA1 form: co-expression with the R31K mutant did not produce the increase seen with wild-type hnRNPA1.[1]
  • The authors noted that whether the candidate proteins are PRMT3 substrates in living systems had not been validated, leaving some proposed substrate relationships unresolved.[1]

PRMT3, hnRNPA1 and ABCG2 in pancreatic cancer cells

Sample size81 tumor tissues[2]
ComparisonPRMT3-overexpressing cells compared with GFP-overexpressing PANC-1 cells; resistant cells compared with parental cells[2]
Main outcomeGemcitabine resistance in pancreatic cancer cells[2]
p-valuep < 0.0001[2]
Times cited71[2]

How later work placed the PRMT3-ABCG2 result

A later review described PRMT3-mediated methylation of hnRNPA1 as promoting its binding to target RNA, placing the proposed mechanism within broader work on RNA-binding proteins.[3]

A 2023 review repeated the proposed link between PRMT3 methylation of hnRNPA1 and ABCG2-associated gemcitabine resistance, while another review noted higher PRMT3 expression in gemcitabine-resistant pancreatic cancer.[4]

Questions left by the cell and tissue evidence

  • Would PRMT3 inhibition change drug sensitivity, rather than only ABCG2 expression, in resistant cells?[1] [2]
  • How closely does the proposed PRMT3–hnRNPA1–ABCG2 sequence in experimental cells reflect the variation among patient tumors?[2]

Terms used in the proposed mechanism

ABCG2
An ABC transporter that can function as a drug efflux pump.[1]

Sources

  1. Protein Arginine Methyltransferase 3 Enhances Chemoresistance in Pancreatic Cancer by Methylating hnRNPA1 to Increase ABCG2 Expression (Europe PMC, 2018)
  2. Protein Arginine Methyltransferase 3 Enhances Chemoresistance in Pancreatic Cancer by Methylating hnRNPA1 to Increase ABCG2 Expression (MDPI AG, 2018)
  3. Arginine methylation of RNA-binding proteins is impaired in Huntington’s disease (2023)
  4. Research progress on PRMTs involved in epigenetic modification and tumour signalling pathway regulation (Review) (2023)

About this Article -

Written with AI assistance from published research, and reviewed by the Mystum team. See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.3390/cancers11010008, Alternate LINK

Title: Protein Arginine Methyltransferase 3 Enhances Chemoresistance In Pancreatic Cancer By Methylating Hnrnpa1 To Increase Abcg2 Expression

Subject: Cancer Research

Journal: Cancers

Publisher: MDPI AG

Authors: Ming-Chuan Hsu, Mei-Ren Pan, Pei-Yi Chu, Ya-Li Tsai, Chia-Hua Tsai, Yan-Shen Shan, Li-Tzong Chen, Wen-Chun Hung

Published: 2018-12-20

Everything You Need To Know

1

What makes pancreatic cancer so difficult to treat?

Pancreatic cancer is a particularly aggressive form of cancer with a very low five-year survival rate. It often goes undetected until it reaches an advanced stage, making effective treatment challenging. Traditional approaches, such as surgical resection, are only viable for a small percentage of patients. For the majority, chemotherapy with Gemcitabine is the primary treatment, but the development of chemoresistance significantly limits its effectiveness.

2

What is the role of PRMT3 in pancreatic cancer?

PRMT3, or protein arginine methyltransferase 3, is an epigenetic modifying enzyme. Research shows that it plays a significant role in pancreatic cancer's resistance to chemotherapy. The study highlighted in the context reveals that PRMT3 is dysregulated in gemcitabine-resistant pancreatic cancer cells. Overexpression of PRMT3 leads to increased resistance to Gemcitabine. Conversely, reducing PRMT3 restored sensitivity to the drug, highlighting its critical role in chemoresistance.

3

What is the significance of ABCG2 in the context of pancreatic cancer treatment?

ABCG2 is a protein, specifically a drug efflux pump, identified as a novel target of PRMT3. This protein actively removes Gemcitabine from cancer cells, thereby reducing the drug's effectiveness. The study shows that PRMT3 increases the expression of ABCG2 by increasing its mRNA stability. This means more ABCG2 protein is produced, leading to greater drug efflux and increased chemoresistance. This is a significant finding, as ABCG2 has been associated with drug resistance in various cancers.

4

How are PRMT3 and ABCG2 related in the process of chemoresistance?

The connection between PRMT3 and ABCG2 lies in how PRMT3 upregulates ABCG2 expression by increasing its mRNA stability. This means PRMT3 helps ABCG2 mRNA last longer, leading to increased production of the ABCG2 protein. ABCG2, acting as a drug efflux pump, actively removes Gemcitabine from the cancer cells, decreasing the drug's effectiveness. This process directly contributes to chemoresistance, a major obstacle in treating pancreatic cancer.

5

What are the implications of these findings for future treatment strategies?

The study's findings open avenues for novel treatment strategies targeting Gemcitabine-resistant pancreatic cancer. By inhibiting PRMT3, researchers aim to reduce ABCG2 expression, thereby restoring the sensitivity of cancer cells to chemotherapy. This approach could significantly improve treatment outcomes for patients, offering a potential breakthrough in managing this challenging disease. This approach has the potential to improve the treatment outcomes for patients.

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