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Cited by 85PI3K/AKT/mTOR signaling in cancerPancreatic and Hepatic Oncology ResearchCancer, Lipids, and Metabolism

Targeting PI3K Pathway in Pancreatic Ductal Adenocarcinoma: Rationale and Progress

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Mehra, Siddharth, Deshpande, Nilesh, Nagathihalli, Nagaraj·2021·Cancers
DOI 10.3390/cancers13174434PMC PMC8430624
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Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest solid tumors that remain treatment-refractory and show a dismal prognosis. More than 90% of PDAC tumors harbor mutations in the K-Ras that exert a strong pro-tumorigenic effect by activating several downstream effector pathways, including phosphatidylinositol-3-kinase (PI3K)-Akt. The role of frequently activated PI3K/Akt pathway in promoting PDAC aggressiveness is well established. Therapeutic approaches targeting PI3K and downstream signaling components in different cellular compartments, including tumor, stromal and immune cells, have directly impacted the tumor burden in this cancer type. Our previous work has demonstrated that targeting the PI3K/Akt/mTOR pathway reduced tumor growth and improved survival in the genetic mouse model of PDAC. Here, we discuss the significance of targeting PI3K signaling and the biological impact of PI3K inhibition in modulating the tumor–stromal immune crosstalk within the microenvironment of pancreatic cancer. Furthermore, this review updates on the current challenges involving the therapeutic implications of targeting this pathway in PDAC.

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  • The PI3K/AKT pathway and increased activity of the Wnt/β-catenin pathway contribute to the mechanisms by which PDAC cells develop drug resistance.

    “the PI3K/AKT pathway and increased activity of the Wnt/β‐catenin pathway contribute to the mechanisms by which PDAC cells develop drug resistance [49, 50]”

    From Pyrvinium Pamoate Alone and With Gemcitabine Exhibits Anti‐Pancreatic Cancer Activity in <scp>2D</scp> and <scp>3D</scp> Cell Culture Models (2024) · cites this paper as [49]

    Section 4 (page unavailable) links PI3K/Akt/mTOR signaling and compensatory pathway activation to therapeutic resistance in PDAC. The cited paper does not establish the claimed contribution of increased Wnt/β-catenin activity to drug resistance. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Mehra, S., Deshpande, N., & Nagathihalli, N.
Affiliations
University of Miami (US)
Corresponding author
Nagathihalli, Nagaraj
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2021-09-02
Volume
13
Issue
17
Pages
4434
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers13174434
PMC
PMC8430624
OpenAlex
W3197296839
Cited by
85
References
4
Citations by year
2026: 13 · 2025: 17 · 2024: 16 · 2023: 25 · 2022: 13 · 2021: 1
FWCI
1.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • American Cancer Society (IRG 98-277-13)
  • National Cancer Institute (R03 CA249401)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
pancreatic ductal adenocarcinoma, PI3K/Akt signaling, PI3K inhibition, KRAS mutation, mTOR, tumor microenvironment, cancer immunotherapy, therapeutic target

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