A Transposon Screen Identifies Loss of Primary Cilia as a Mechanism of Resistance to SMO Inhibitors

Zhao, Xuesong; Pak, Ekaterina; Ornell, Kimberly J.; Pazyra-Murphy, Maria F.; MacKenzie, Ethan L.; Chadwick, Emily J.; Ponomaryov, Tatyana; Kelleher, Joseph F.; Segal, Rosalind A.

doi:10.1158/2159-8290.cd-17-0281

Cited by 51 publications

(59 citation statements)

References 33 publications

(44 reference statements)

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“…[160,161] Two SMO inhibitors, vismodegib and sonidegib, have been approved by the U.S. Food and Drug Administration for treatment in advanced or metastatic BCC. [160,161] Two SMO inhibitors, vismodegib and sonidegib, have been approved by the U.S. Food and Drug Administration for treatment in advanced or metastatic BCC.…”

Section: Hedgehog Signaling Regulates Cancer Cell Proliferation Throumentioning

confidence: 99%

“…[160,161] Two SMO inhibitors, vismodegib and sonidegib, have been approved by the U.S. Food and Drug Administration for treatment in advanced or metastatic BCC. [160] The mutations in ciliary genes cause the loss of primary cilia on SHH medulloblastoma cells and confer resistance to SMO inhibitors due to the lack of GLI-R and the presence of full-length GLI2, the latter of which can work as a weak transcriptional activator without SMO signaling. Despite good initial responses, mutation-related resistance to the SMO inhibitors often emerges.…”

Section: Hedgehog Signaling Regulates Cancer Cell Proliferation Throumentioning

confidence: 99%

“…Several other SMO inhibitors have also been developed in clinical trials for treatment in medulloblastoma. [160] Additional mutations, such as loss-of-function mutations in SUFU, increase the nuclear transport of GLI2 and enhance hedgehog signaling, resulting in the aggressive growth of medulloblastoma and BCC resistant to SMO inhibitors. [162] Although most mutations are observed in the drug-binding pocket of SMO, mutations in genes related to ciliogenesis, including OFD1, IFT80, and retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1), have also been identified.…”

Section: Hedgehog Signaling Regulates Cancer Cell Proliferation Throumentioning

confidence: 99%

“…Despite good initial responses, mutation-related resistance to the SMO inhibitors often emerges. [160,163,164] Several strategies can be considered to overcome this drug resistance, including the inhibition of GLI-A and reintroduction of primary cilia. [160] The mutations in ciliary genes cause the loss of primary cilia on SHH medulloblastoma cells and confer resistance to SMO inhibitors due to the lack of GLI-R and the presence of full-length GLI2, the latter of which can work as a weak transcriptional activator without SMO signaling.…”

Section: Hedgehog Signaling Regulates Cancer Cell Proliferation Throumentioning

confidence: 99%

“…[162] Although most mutations are observed in the drug-binding pocket of SMO, mutations in genes related to ciliogenesis, including OFD1, IFT80, and retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1), have also been identified. [160,161] Small molecules have been identified that inhibit GLI-A [162,[165][166][167][168][169][170][171] and reintroduce primary cilia. [160] Additional mutations, such as loss-of-function mutations in SUFU, increase the nuclear transport of GLI2 and enhance hedgehog signaling, resulting in the aggressive growth of medulloblastoma and BCC resistant to SMO inhibitors.…”

Section: Hedgehog Signaling Regulates Cancer Cell Proliferation Throumentioning

confidence: 99%

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Primary Cilia as Signaling Hubs in Health and Disease

et al. 2018

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Primary cilia detect extracellular cues and transduce these signals into cells to regulate proliferation, migration, and differentiation. Here, the function of primary cilia as signaling hubs of growth factors and morphogens is in focus. First, the molecular mechanisms regulating the assembly and disassembly of primary cilia are described. Then, the role of primary cilia in mediating growth factor and morphogen signaling to maintain human health and the potential mechanisms by which defects in these pathways contribute to human diseases, such as ciliopathy, obesity, and cancer are described. Furthermore, a novel signaling pathway by which certain growth factors stimulate cell proliferation through suppression of ciliogenesis is also described, suggesting novel therapeutic targets in cancer.

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Section: Hedgehog Signaling Regulates Cancer Cell Proliferation Throumentioning

confidence: 99%

Section: Hedgehog Signaling Regulates Cancer Cell Proliferation Throumentioning

confidence: 99%

Section: Hedgehog Signaling Regulates Cancer Cell Proliferation Throumentioning

confidence: 99%

Section: Hedgehog Signaling Regulates Cancer Cell Proliferation Throumentioning

confidence: 99%

Section: Hedgehog Signaling Regulates Cancer Cell Proliferation Throumentioning

confidence: 99%

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Primary Cilia as Signaling Hubs in Health and Disease

et al. 2018

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Increased Risk of Cutaneous Squamous Cell Carcinoma After Vismodegib Therapy for Basal Cell Carcinoma

et al. 2016

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IMPORTANCE Smoothened inhibitors (SIs) are a new type of targeted therapy for advanced basal cell carcinoma (BCC), and their long-term effects, such as increased risk of subsequent malignancy, are still being explored. OBJECTIVE To evaluate the risk of developing a non-BCC malignancy after SI exposure in patients with BCC. DESIGN, SETTING, AND PARTICIPANTS A case-control study at Stanford Medical Center, an academic hospital. Participants were higher-risk patients with BCC diagnosed from January 1, 1998, to December 31, 2014. The dates of the analysis were January 1 to November 1, 2015. EXPOSURES The exposed participants (cases) comprised patients who had confirmed prior vismodegib treatment, and the nonexposed participants (controls) comprised patients who had never received any SI. Because vismodegib was the first approved SI, only patients exposed to this SI were included. MAIN OUTCOMES AND MEASURES Hazard ratio for non-BCC malignancies after vismodegib exposure, adjusting for covariates. RESULTS The study cohort comprised 180 participants. Their mean (SD) age at BCC diagnosis was 56 (16) years, and 68.9% (n = 124) were male. Fifty-five cases were compared with 125 controls, accounting for age, sex, prior radiation therapy or cisplatin treatment, Charlson Comorbidity Index, clinical follow-up time, immunosuppression, and basal cell nevus syndrome status. Patients exposed to vismodegib had a hazard ratio of 6.37 (95% CI, 3.39-11.96; P < .001), indicating increased risk of developing a non-BCC malignancy. Most non-BCC malignancies were cutaneous squamous cell carcinomas, with a hazard ratio of 8.12 (95% CI, 3.89-16.97; P < .001), accounting for age and basal cell nevus syndrome status. There was no significant increase in other cancers. CONCLUSIONS AND RELEVANCE Increased risk for cutaneous squamous cell carcinomas after vismodegib therapy highlights the importance of continued skin surveillance after initiation of this therapy.

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Genetic variants in primary cilia‐related genes associated with the prognosis of first‐line chemotherapy in colorectal cancer

Qiu,

Chen,

Ben

et al. 2024

Cancer Medicine

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BackgroundPrimary cilia are antenna‐like organelles that conduct physical and chemical signals, which affect cell proliferation, migration, and differentiation. Some researchers have reported the correlation between primary cilia‐related genes and prognosis of colorectal cancer (CRC).MethodsThe association between single nucleotide polymorphisms (SNPs) of primary cilia‐related genes and outcome after the first‐line chemotherapy was explored by the Cox regression model. Expression qualitative trait locus (eQTL) analysis was performed to explore the impact of SNPs on gene expression. Tumor Immune Estimation Resource and TISIDB databases were used for investigating the relevance between ODF2L and tumor infiltration immune cells and immunomodulators.ResultsWe identified that rs4288473 C allele of ODF2L had poor progression‐free survival (PFS) and overall survival (OS) of CRC patients in the additive model (adjusted HRPFS = 1.39, 95% CI = 1.14–1.70, p = 1.36 × 10−3, and adjusted HROS = 1.31, 95% CI = 1.03–1.65, p = 2.62 × 10−2). The stratified analysis indicated that rs4288573 CC/CT genotype was involved with poor prognosis in the irinotecan‐treated subgroup (PPFS = 1.03 × 10−2, POS = 3.29 × 10−3). Besides, ODF2L mRNA expression level was notably up‐regrated in CRC tissues. The C allele of rs4288573 was notably related to higher ODF2L mRNA expression levels based on eQTL analysis. Functionally, knockdown of ODF2L inhibited cell proliferation and decrease the chemoresistance of HCT‐116 and DLD‐1 cells to irinotecan.ConclusionOur study indicates that rs4288573 in ODF2L is a potential predictor of the chemotherapy prognosis of CRC.

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A Transposon Screen Identifies Loss of Primary Cilia as a Mechanism of Resistance to SMO Inhibitors

Cited by 51 publications

References 33 publications

Primary Cilia as Signaling Hubs in Health and Disease

Primary Cilia as Signaling Hubs in Health and Disease

Increased Risk of Cutaneous Squamous Cell Carcinoma After Vismodegib Therapy for Basal Cell Carcinoma

Genetic variants in primary cilia‐related genes associated with the prognosis of first‐line chemotherapy in colorectal cancer

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