Immune vulnerabilities of mutant KRAS in pancreatic cancer

Cheng, Noah; Vonderheide, Robert H.

doi:10.1016/j.trecan.2023.07.004

Cited by 5 publications

(3 citation statements)

References 79 publications

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“…The origin of CAFs remains unclear with a minority produced from the pancreatic stellate cell ( 59 ). Immunosuppressive and immune-enhancing CAFs exist ( 60 ), however oncogenic KRAS promotes non-cell autonomous programming of CAFs to stimulate cytokines, which regulate MDSCs and other immune cells ( 61 ). Understanding the pleiotropic effects of KRAS mutations in molding the TME early in oncogenesis will be critical in trial design of combination approaches in PDAC.…”

Section: Impact Of Kras Signaling On the Tumor Microenvironment And S...mentioning

confidence: 99%

Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies

Linehan,

O’Reilly,

McDermott

et al. 2024

Front. Med.

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Targeting the RAS pathway remains the holy grail of precision oncology. In the case of pancreatic ductal adenocarcinomas (PDAC), 90–92% harbor mutations in the oncogene KRAS, triggering canonical MAPK signaling. The smooth structure of the altered KRAS protein without a binding pocket and its affinity for GTP have, in the past, hampered drug development. The emergence of KRASG12C covalent inhibitors has provided renewed enthusiasm for targeting KRAS. The numerous pathways implicated in RAS activation do, however, lead to the development of early resistance. In addition, the dense stromal niche and immunosuppressive microenvironment dictated by oncogenic KRAS can influence treatment responses, highlighting the need for a combination-based approach. Given that mutations in KRAS occur early in PDAC tumorigenesis, an understanding of its pleiotropic effects is key to progress in this disease. Herein, we review current perspectives on targeting KRAS with a focus on PDAC.

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Section: Impact Of Kras Signaling On the Tumor Microenvironment And S...mentioning

confidence: 99%

Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies

Linehan,

O’Reilly,

McDermott

et al. 2024

Front. Med.

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“…Mutant K-RAS plays a critical role in the immunosuppression of PDAC microenvironment [ 74 , 75 , 76 ]. Thus, immunologically, mutant K-RAS has an equally important target [ 77 , 78 , 79 ]. Despite having mixed and descriptive information on T-helper 2 (Th2) cells and associated cytokines in cancer, recent studies have found that Th2 cells may be crucial regulators of colon and pancreas cancer progression by affecting immune cell composition and type II immune responses.…”

Section: Tunicamycin In Cancer Therapymentioning

confidence: 99%

Benefits and Pitfalls of a Glycosylation Inhibitor Tunicamycin in the Therapeutic Implication of Cancers

Banerjee,

Ansari,

Upadhyay

et al. 2024

Cells

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The aberrant glycosylation is a hallmark of cancer progression and chemoresistance. It is also an immune therapeutic target for various cancers. Tunicamycin (TM) is one of the potent nucleoside antibiotics and an inhibitor of aberrant glycosylation in various cancer cells, including breast cancer, gastric cancer, and pancreatic cancer, parallel with the inhibition of cancer cell growth and progression of tumors. Like chemotherapies such as doxorubicin (DOX), 5′fluorouracil, etoposide, and cisplatin, TM induces the unfolded protein response (UPR) by blocking aberrant glycosylation. Consequently, stress is induced in the endoplasmic reticulum (ER) that promotes apoptosis. TM can thus be considered a potent antitumor drug in various cancers and may promote chemosensitivity. However, its lack of cell-type-specific cytotoxicity impedes its anticancer efficacy. In this review, we focus on recent advances in our understanding of the benefits and pitfalls of TM therapies in various cancers, including breast, colon, and pancreatic cancers, and discuss the mechanisms identified by which TM functions. Finally, we discuss the potential use of nano-based drug delivery systems to overcome non-specific toxicity and enhance the therapeutic efficacy of TM as a targeted therapy.

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“…Furthermore, the intratumoral heterogeneity poses a challenge to PDAC vaccine development in which tumor-associated antigen targeting would be useful. Nevertheless, messenger RNA (mRNA) vaccines show promise in pancreatic cancer as a personalized therapy by encoding customized proteins based on the genetic profile of an individual's tumors, specifically mutant Kras [36,39]. Additionally, a recent phase I trial evaluated the efficacy of personalized RNA neoantigen vaccines.…”

Section: Ici Reverses T-cell Dysfunction and Enhances Neoantigen Vacc...mentioning

confidence: 99%

The Prospect of Harnessing the Microbiome to Improve Immunotherapeutic Response in Pancreatic Cancer

Rogers,

Charles,

Thomas

2023

Cancers

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Pancreatic ductal adenocarcinoma cancer (PDAC) is projected to become the second leading cause of cancer-related death in the United States by 2030. Patients are often diagnosed with advanced disease, which explains the dismal 5-year median overall survival rate of ~12%. Immunotherapy has been successful in improving outcomes in the past decade for a variety of malignancies, including gastrointestinal cancers. However, PDAC is historically an immunologically “cold” tumor, one with an immunosuppressive environment and with restricted entry of immune cells that have limited the success of immunotherapy in these tumors. The microbiome, the intricate community of microorganisms present on and within humans, has been shown to contribute to many cancers, including PDAC. Recently, its role in tumor immunology and response to immunotherapy has generated much interest. Herein, the current state of the interaction of the microbiome and immunotherapy in PDAC is discussed with a focus on needed areas of study in order to harness the immune system to combat pancreatic cancer.

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Immune vulnerabilities of mutant KRAS in pancreatic cancer

Cited by 5 publications

References 79 publications

Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies

Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies

Benefits and Pitfalls of a Glycosylation Inhibitor Tunicamycin in the Therapeutic Implication of Cancers

The Prospect of Harnessing the Microbiome to Improve Immunotherapeutic Response in Pancreatic Cancer

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