Dual Phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor is an effective radiosensitizer for colorectal cancer

Chen, Yu-Hsuan; Wei, Ming Feng; Wang, Chun Wei; Lee, Hsiao Wei; Pan, Shiow Lin; Gao, Ming; Kuo, Sung‐Hsin; Cheng, Ann‐Lii; Teng, Che-Ming

doi:10.1016/j.canlet.2014.12.015

Cited by 44 publications

(44 citation statements)

References 35 publications

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“…Interestingly the two patients with both PIK3CA and BRAF mutations progressed locally faster (within 3 months) than patients with only PIK3CA mutations or combined PIK3CA and KRAS mutations, pointing to either differing radio-sensitivity of BRAF and KRAS mutations or other complex interactions via cross-talk between the MAPK and PI3K pathways [28]. PI3K pathway inhibitors are associated with radio-sensitivity [29], suggesting a potential role for adjuvant therapy at the time of RE.…”

Section: Discussionmentioning

confidence: 99%

PI3K pathway mutations are associated with longer time to local progression after radioembolization of colorectal liver metastases

et al. 2017

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PurposeTo establish the relationship between common mutations in the MAPK and PI3K signaling pathways and local progression after radioembolization.Materials and MethodsRetrospective review of a HIPAA-compliant institutional review-board approved database identified 40 patients with chemo-refractory colorectal liver metastases treated with radioembolization who underwent tumor genotyping for hotspot mutations in 6 key genes in the MAPK/PI3K pathways (KRAS, NRAS, BRAF, MEK1, PIK3CA, and AKT1). Mutation status as well as clinical, tumor, and treatment variables were recorded. These factors were evaluated in relation to time to local progression (TTLP), which was calculated from time of radioembolization to first radiographic evidence of local progression. Predictors of outcome were identified using a proportional hazards model for both univariate and multivariate analysis with death as a competing risk.ResultsSixteen patients (40%) had no mutations in either pathway, eighteen patients (45%) had mutations in the MAPK pathway, ten patients (25%) had mutations in the PI3K pathway and four patients (10%) had mutations in both pathways. The cumulative incidence of progression at 6 and 12 months was 33% and 55% for the PI3K mutated group compared with 76% and 92% in the PI3K wild type group. Mutation in the PI3K pathway was a significant predictor of longer TTLP in both univariate (p=0.031, sHR 0.31, 95% CI: 0.11-0.90) and multivariate (p=0.015, sHR=0.27, 95% CI: 0.096-0.77) analysis. MAPK pathway alterations were not associated with TTLP.ConclusionsPI3K pathway mutation predicts longer time to local progression after radioembolization of colorectal liver metastases.

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Section: Discussionmentioning

confidence: 99%

PI3K pathway mutations are associated with longer time to local progression after radioembolization of colorectal liver metastases

et al. 2017

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“…One logical outcome of this argument is that chloroquine and hydroxychloroquine are unlikely to be appropriate drugs for this purpose, because of the fact that patients with malaria are able to endure treatment with these drugs for years, which suggests that the doses of chloroquine and hydroxychloroquine that are used effectively for malaria treatment may not actually be acting to inhibit autophagy. Another logical outcome is that various studies indicated that the sensitivity of tumor cells to radiation could be enhanced by co-treatment with rapamycin, an autophagy promoter, in various kinds of tumor cells (44,50,127).…”

Section: Targeting Autophagy For Radiotherapymentioning

confidence: 99%

Crosstalk between autophagy and intracellular radiation response (Review)

Wang

Huang

et al. 2016

International Journal of Oncology

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Abstract. Autophagy induced by radiation is critical to cell fate decision. Evidence now sheds light on the importance of autophagy induced by cancer radiotherapy. Traditional view considers radiation can directly or indirectly damage DNA which can activate DNA damage the repair signaling pathway, a large number of proteins participating in DNA damage repair signaling pathway such as p53, ATM, PARP1, FOXO3a, mTOR and SIRT1 involved in autophagy regulation. However, emerging recent evidence suggests radiation can also cause injury to extranuclear targets such as plasma membrane, mitochondria and endoplasmic reticulum (ER) and induce accumulation of ceramide, ROS, and Ca 2+ concentration which activate many signaling pathways to modulate autophagy. Herein we review the role of autophagy in radiation therapy and the potent intracellular autophagic triggers induced by radiation. We aim to provide a more theoretical basis of radiation-induced autophagy, and provide novel targets for developing cytotoxic drugs to increase radiosensitivity. Contents1. Introduction 2. The role of autophagy in radiotherapy 3. DNA damage repair and autophagy 4. Mitochondrial damage and autophagy 5. ER stress and autophagy 6. ROS and autophagy 7. Ceramide and autophagy 8. Ca 2+ and autophagy 9. Targeting autophagy for radiotherapy 10. Conclusion IntroductionRadiotherapy is an effective strategy for the treatment of many kinds of cancer to kill or control the malignant tumor cells. However, its benefits have been limited due to radiation resistance. It is imperative to identify new targets and develop cytotoxic drugs to increase radiosensitivity. Radiosensitization has traditionally been performed with agents known to induce apoptosis. However, recent studies demonstrate autophagy induced by radiation also plays an important role in cancer Crosstalk between autophagy and intracellular radiation response (Review)

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“…Activation of PI3K/AKT signaling pathway can promote cell proliferation, inhibit apoptosis, promote cell cycle progression, and promote cell invasion and metastasis, which play an important role in radiation induced cancer cell resistance and normal cell injury. After irradiation, some cancer cells activated PI3K/AKT pathway, inducing radiation resistance to reduce the radiation sensitivity. But PI3K/AKT signaling pathway was inhibited in normal cells after radiation ,.…”

Section: Discussionmentioning

confidence: 99%

A new and important relationship between miRNA‐147a and PDPK1 in radiotherapy

Wang

et al. 2018

J of Cellular Biochemistry

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It was found that the expression level of miR-147a was significantly increased and the pathway of PI3K/AKT was dramatically inhibited after radiation. In view of the relationship between miRNA and target genes, we put forward the question, what is the relationship between PI3K/AKT and miR-147a? In order to find the answer to the question, we used bioinformatics techniques to analyze the relationship between miR- 147 (a or b) and PI3K/AKT signaling pathway. miR-147a overexpression plasmid and PDPK1 3′UTR luciferase reporter gene plasmid were constructed. Dual luciferase reporter gene system validation experiments were carried out on miR-147a and PDPK1 relationship. The verification experiments were also carried out. Bioinformatics analysis showed that there is a miR-147a binding site in the non-coding region (3′UTR) of PDPK1. In the experimental groups transfected with wild type PDPK1 gene of 3′UTR plasmid, the luciferase activity decreased (or increased) significantly in miR-147a (or inhibitor) group compared with miR-NC (or anti-miR-NC); There was no significant difference between the miR-147a group (or inhibitor) and the miR-NC group (or anti- miR-NC) in the transfection of PDPK1–3′UTR-Mut gene vector. PDPK1 was a target gene for direct regulation of miR-147a downstream. Verifying test results showed that the expression of PDPK1 mRNA and protein was reduced after overexpression of miR-147a, which was up-regulated after silencing miR-147a in TC, and V79 cells. These results suggest that miR-147a could be involved in the regulation of PDPK1 transcription by binding to the target site in PDPK1 mRNA 3′UTR, and then regulated AKT.

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Dual Phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor is an effective radiosensitizer for colorectal cancer

Cited by 44 publications

References 35 publications

PI3K pathway mutations are associated with longer time to local progression after radioembolization of colorectal liver metastases

PI3K pathway mutations are associated with longer time to local progression after radioembolization of colorectal liver metastases

Crosstalk between autophagy and intracellular radiation response (Review)

A new and important relationship between miRNA‐147a and PDPK1 in radiotherapy

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