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Barriers and opportunities for gemcitabine in pancreatic cancer therapy.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) has become one of the leading causes of cancer-related deaths across the world. A lack of durable responses to standard-of-care chemotherapies renders its treatment particularly challenging and largely contributes to the devastating outcome. Gemcitabine, a pyrimidine antimetabolite, is a cornerstone in PDA treatment. Given the importance of gemcitabine in PDA therapy, extensive efforts are focusing on exploring mechanisms by which cancer cells evade gemcitabine cytotoxicity, but strategies to overcome them have not been translated into patient care. Here, we will introduce the standard treatment paradigm for patients with PDA, highlight mechanisms of gemcitabine action, elucidate gemcitabine resistance mechanisms, and discuss promising strategies to circumvent them.

SUBMITTER: Beutel AK

PROVIDER: S-EPMC9925166 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Barriers and opportunities for gemcitabine in pancreatic cancer therapy.

Beutel Alica K AK Halbrook Christopher J CJ

American journal of physiology. Cell physiology 20221226 2

Pancreatic ductal adenocarcinoma (PDA) has become one of the leading causes of cancer-related deaths across the world. A lack of durable responses to standard-of-care chemotherapies renders its treatment particularly challenging and largely contributes to the devastating outcome. Gemcitabine, a pyrimidine antimetabolite, is a cornerstone in PDA treatment. Given the importance of gemcitabine in PDA therapy, extensive efforts are focusing on exploring mechanisms by which cancer cells evade gemcita ...[more]

PMID: 36571444

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Project description:BackgroundPancreatic cancer retains a poor prognosis among the gastrointestinal cancers. It affects 230,000 individuals worldwide, has a very high mortality rate, and remains one of the most challenging malignancies to treat successfully. Treatment with gemcitabine, the most widely used chemotherapeutic against pancreatic cancer, is not curative and resistance may occur. Combinations of gemcitabine with other chemotherapeutic drugs or biological agents have resulted in limited improvement.MethodsIn order to improve gemcitabine response in pancreatic cancer cells, we utilized a synthetic lethal RNAi screen targeting 572 known kinases to identify genes that when silenced would sensitize pancreatic cancer cells to gemcitabine.ResultsResults from the RNAi screens identified several genes that, when silenced, potentiated the growth inhibitory effects of gemcitabine in pancreatic cancer cells. The greatest potentiation was shown by siRNA targeting checkpoint kinase 1 (CHK1). Validation of the screening results was performed in MIA PaCa-2 and BxPC3 pancreatic cancer cells by examining the dose response of gemcitabine treatment in the presence of either CHK1 or CHK2 siRNA. These results showed a three to ten-fold decrease in the EC50 for CHK1 siRNA-treated cells versus control siRNA-treated cells while treatment with CHK2 siRNA resulted in no change compared to controls. CHK1 was further targeted with specific small molecule inhibitors SB 218078 and PD 407824 in combination with gemcitabine. Results showed that treatment of MIA PaCa-2 cells with either of the CHK1 inhibitors SB 218078 or PD 407824 led to sensitization of the pancreatic cancer cells to gemcitabine.ConclusionThese findings demonstrate the effectiveness of synthetic lethal RNAi screening as a tool for identifying sensitizing targets to chemotherapeutic agents. These results also indicate that CHK1 could serve as a putative therapeutic target for sensitizing pancreatic cancer cells to gemcitabine.

Dataset Information

Barriers and opportunities for gemcitabine in pancreatic cancer therapy.

Publications

Barriers and opportunities for gemcitabine in pancreatic cancer therapy.

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