Defining the Role of GLI/Hedgehog Signaling in Chemoresistance: Implications in Therapeutic Approaches

Chai, Jian Yi; Sugumar, Vaisnevee; Al-Shanon, Ahmed F.; Wong, Won Fen; Fung, Shin Yee; Looi, Chung Yeng

doi:10.3390/cancers13194746

Cited by 14 publications

(20 citation statements)

References 166 publications

(210 reference statements)

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“…The combination of MK-0752 with dalotuzumab effectively inhibited cell proliferation, angiogenesis, and stem cell propagation in a phase I trial. Likewise, the combination of MK-0752 and docetaxel is used against advanced breast cancer [ 128 ].…”

Section: Pathways Associated With Glioma and Glioblastomamentioning

confidence: 99%

Progress in Glioma Stem Cell Research

Ramar,

Guo,

Hudson

et al. 2023

Cancers

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Glioblastoma multiforme (GBM) represents a diverse spectrum of primary tumors notorious for their resistance to established therapeutic modalities. Despite aggressive interventions like surgery, radiation, and chemotherapy, these tumors, due to factors such as the blood–brain barrier, tumor heterogeneity, glioma stem cells (GSCs), drug efflux pumps, and DNA damage repair mechanisms, persist beyond complete isolation, resulting in dismal outcomes for glioma patients. Presently, the standard initial approach comprises surgical excision followed by concurrent chemotherapy, where temozolomide (TMZ) serves as the foremost option in managing GBM patients. Subsequent adjuvant chemotherapy follows this regimen. Emerging therapeutic approaches encompass immunotherapy, including checkpoint inhibitors, and targeted treatments, such as bevacizumab, aiming to exploit vulnerabilities within GBM cells. Nevertheless, there exists a pressing imperative to devise innovative strategies for both diagnosing and treating GBM. This review emphasizes the current knowledge of GSC biology, molecular mechanisms, and associations with various signals and/or pathways, such as the epidermal growth factor receptor, PI3K/AKT/mTOR, HGFR/c-MET, NF-κB, Wnt, Notch, and STAT3 pathways. Metabolic reprogramming in GSCs has also been reported with the prominent activation of the glycolytic pathway, comprising aldehyde dehydrogenase family genes. We also discuss potential therapeutic approaches to GSC targets and currently used inhibitors, as well as their mode of action on GSC targets.

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Section: Pathways Associated With Glioma and Glioblastomamentioning

confidence: 99%

Progress in Glioma Stem Cell Research

Ramar,

Guo,

Hudson

et al. 2023

Cancers

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“…Studies have also revealed the role of plasticity-mediated drug resistance in cancer cells [83] via the Hh pathway through the upregulation of different proteins like OCT4, BMI 1 and SOX 2, which increased stemness and drug resistance [84]. In studies by Magistri et al and Nguyen et al, it was observed that Smoothened (SMO) inhibition leads to the overexpression of two Hh target genes, GL1 and GL2, which are the transcription factors responsible for the upregulation of the master gene Snail that is known for promoting plasticity in the cancer cells [85].…”

Section: Drug Resistance Mediated By Cancer Cell Plasticitymentioning

confidence: 99%

“…Studies have also revealed the role of plasticity‐mediated drug resistance in cancer cells [83] via the Hh pathway through the upregulation of different proteins like OCT4 , BMI 1 and SOX 2 , which increased stemness and drug resistance [84]. In studies by Magistri et al.…”

Section: Drug Resistance Mediated By Cancer Cell Plasticitymentioning

confidence: 99%

Unraveling the dangerous duet between cancer cell plasticity and drug resistance

Chatterjee,

Pulipaka,

Subbalakshmi

et al. 2023

Comp Sys Onco

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Cancer cell plasticity is the ability of tumor cells to switch phenotypes and is one of the predominant requisites of cancer cells capable of undergoing metastasis. Cancer cell plasticity is also recognized as one of the major contributors to intratumoral heterogeneity, a critical factor underlying the progression of malignant tumors, which is known to modify tumor response and induce resistance against various modes of therapy, thus posing a barrier to efficient cancer management. Cancer cell plasticity is acquired by the subversion of cell signaling pathways like mitogen‐activated protein kinase pathway, phosphoinositide‐3‐kinase, signal transducer and activator of transcription 3, Wnt, Hedgehog and Notch as well as cellular programs such as epithelial to mesenchymal transition and phenotypic plasticity. This complex phenomenon has been studied in many cancer types like pancreatic cancer, colon cancer and breast cancer. This review will explore the current understanding we have in breast cancer on the intrinsic molecular mechanisms of cancer cell plasticity and the resistance to various types of cancer therapy that arise as a result of plasticity. We conclude by exploring the potential novel therapies that specifically target the pathways leading to plasticity and can be leveraged to treat patients living with the disease.

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“…Similarly, targeting the Wnt/β-catenin pathway can inhibit CSC self-renewal and metastasis in TNBC [ 40 ]. Inhibition of the Hedgehog pathway reduces CSC frequency and sensitivity to chemotherapy [ 41 ]. Moreover, targeting the TGF-β pathway has been shown to sensitize TNBC cells to chemotherapy and inhibit the EMT process [ 42 ].…”

Section: Signaling Pathways Involved In Cscs Plasticity In Tnbcmentioning

confidence: 99%

Targeting cancer stem cell plasticity in triple-negative breast cancer

Guo,

Han

2023

Exploration of Targeted Anti-Tumor Therapy

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Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited treatment options. Cancer stem cells (CSCs) are thought to play a crucial role in TNBC progression and resistance to therapy. CSCs are a small subpopulation of cells within tumors that possess self-renewal and differentiation capabilities and are responsible for tumor initiation, maintenance, and metastasis. CSCs exhibit plasticity, allowing them to switch between states and adapt to changing microenvironments. Targeting CSC plasticity has emerged as a promising strategy for TNBC treatment. This review summarizes recent advances in understanding the molecular mechanisms underlying CSC plasticity in TNBC and discusses potential therapeutic approaches targeting CSC plasticity.

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Defining the Role of GLI/Hedgehog Signaling in Chemoresistance: Implications in Therapeutic Approaches

Cited by 14 publications

References 166 publications

Progress in Glioma Stem Cell Research

Progress in Glioma Stem Cell Research

Unraveling the dangerous duet between cancer cell plasticity and drug resistance

Targeting cancer stem cell plasticity in triple-negative breast cancer

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