Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Wu, Xianbo; Xu, Yunyun; Liang, Qi; Yang, Xinwei; Huang, Jianli; Wang, Jie; Zhang, Hong; Shi, Jianyou

doi:10.3389/fphar.2022.875372

Cited by 38 publications

(15 citation statements)

References 111 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have shown that the PI3K/AKT/mTOR pathway modulates cell cycle, apoptosis, autophagy, angiogenesis, EMT, and chemoresistance in cancers (45,46). Additionally, drugs targeting the PI3K/AKT/mTOR pathway in combination with chemotherapeutic drugs are considered promising treatment approaches (47). Several genes have been reported to in uence cell cycle, apoptosis, migration, and invasion via the PI3K/AKT/mTOR signaling pathway in cancer (48-50).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of TFRC suppressed the progression of nasopharyngeal carcinoma by downregulating the PI3K/Akt/mTOR pathway

Feng

Arima

Midorikawa

et al. 2023

Preprint

View full text Add to dashboard Cite

Background The transferrin receptor (TfR) encoded by TFRC gene is the main cellular iron importer. TfR is highly expressed in many cancers and is expected to be a promising new target for cancer therapy; however, its role in nasopharyngeal carcinoma (NPC) remains unknown. Methods The TfR levels were investigated in NPC tissues and cell lines using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. Knockdown of TFRC using two siRNA to investigate the effects on intracellular iron level and biological functions, including proliferation by CKK-8 assay, colony formation, cell apoptosis and cell cycle by flow cytometry, migration and invasion, and tumor growth in vivo by nude mouse xenografts. RNA sequencing was performed to find possible mechanism after TFRC knockdown on NPC cells and further verify by western blotting. Results TfR is overexpressed in NPC cell lines and tissues. Knockdown of TFRC inhibited cell proliferation concomitant with increased apoptosis and cell cycle arrest and decreased intracellular iron, colony formation, migration, invasion, and epithelial mesenchymal transition in HK1-EBV cells. Western blotting showed that TFRC knockdown suppressed the levels of the iron storage protein FTH1, anti-apoptotic marker BCL-xL, and epithelial–mesenchymal transition markers. We confirmed in vivo that TFRC knockdown also inhibited NPC tumor growth and decreased Ki67 expression in tumor tissues of nude mouse xenografts. RNA sequencing and western blotting revealed that TFRC silencing inhibits the PI3K/Akt/mTOR signaling pathway. Conclusions These results indicated that TfR was overexpressed in NPC, and TFRC knockdown inhibited NPC progression by suppressing the PI3K/Akt/mTOR signaling pathway. Thus, TfR may serve as a novel biomarker and therapeutic target for NPC.

show abstract

Section: Discussionmentioning

confidence: 99%

Knockdown of TFRC suppressed the progression of nasopharyngeal carcinoma by downregulating the PI3K/Akt/mTOR pathway

Feng

Arima

Midorikawa

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…In line with this, we have seen in our study that MCF7 MAGI1 KO cells are more sensitive against the combination of alpelisib and fulvestrant than MCF7 VEC cells. In addition, to evade the activation of feedback loops, the combination of dual inhibitors against PI3K and mTOR (reviewed in [134]), as well as the simultaneous inhibition of the MAPK together with PI3K/mTOR signaling pathways [135], have shown efficacy in selected tumor types. Whether or not this triple combination could benefit patients with low MAGI1 levels would require further investigation.…”

Section: Discussionmentioning

confidence: 99%

MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER+ Breast Cancer

Wörthmüller,

Disler,

Pradervand

et al. 2023

Cells

View full text Add to dashboard Cite

MAGI1 acts as a tumor suppressor in estrogen receptor-positive (ER+) breast cancer (BC), and its loss correlates with a more aggressive phenotype. To identify the pathways and events affected by MAGI1 loss, we deleted the MAGI1 gene in the ER+ MCF7 BC cell line and performed RNA sequencing and functional experiments in vitro. Transcriptome analyses revealed gene sets and biological processes related to estrogen signaling, the cell cycle, and DNA damage responses affected by MAGI1 loss. Upon exposure to TNF-α/IFN-γ, MCF7 MAGI1 KO cells entered a deeper level of quiescence/senescence compared with MCF7 control cells and activated the AKT and MAPK signaling pathways. MCF7 MAGI1 KO cells exposed to ionizing radiations or cisplatin had reduced expression of DNA repair proteins and showed increased sensitivity towards PARP1 inhibition using olaparib. Treatment with PI3K and AKT inhibitors (alpelisib and MK-2206) restored the expression of DNA repair proteins and sensitized cells to fulvestrant. An analysis of human BC patients’ transcriptomic data revealed that patients with low MAGI1 levels had a higher tumor mutational burden and homologous recombination deficiency. Moreover, MAGI1 expression levels negatively correlated with PI3K/AKT and MAPK signaling, which confirmed our in vitro observations. Pharmacological and genomic evidence indicate HDACs as regulators of MAGI1 expression. Our findings provide a new view on MAGI1 function in cancer and identify potential treatment options to improve the management of ER+ BC patients with low MAGI1 levels.

show abstract

“…Dual AKT/mTORC1 targeting in preclinical models impedes double-strand break repair and primes cancer cells for sensitivity to subsequent DNA damaging therapy (24). Successful inhibition of the PAM pathway following selective inhibition of PI3Kα and mTORC1/mTORC2 has been shown to sensitize breast cancers to taxane or platinum-based therapies (25).…”

Section: Tak-228 (Formerly Ink128 and Mln0128mentioning

confidence: 99%

Pilot clinical trial and phenotypic analysis in chemotherapy-pretreated, metastatic triple-negative breast cancer patients treated with oral TAK-228 and TAK-117 (PIKTOR) to increase DNA damage repair deficiency followed by cisplatin and nab paclitaxel

Lang

Nguyen

Levin

et al. 2023

Preprint

View full text Add to dashboard Cite

BACKGROUND A subset of triple-negative breast cancers (TNBCs) have homologous recombination deficiency with upregulation of compensatory DNA repair pathways. PIKTOR, a combination of TAK-228 (TORC1/2 inhibitor) and TAK-117 (PI3Kα inhibitor), is hypothesized to increase genomic instability and increase DNA damage repair (DDR) deficiency, leading to increased sensitivity to DNA-damaging chemotherapy and to immune checkpoint blockade inhibitors.METHODS 10 metastatic TNBC patients received 4mg TAK-228 and 200mg TAK-117 (PIKTOR) orally each day for 3 days followed by 4 days off, weekly, until disease progression (PD), followed by intravenous cisplatin 75 mg/m2 plus nab paclitaxel 220 mg/m2 every 3 weeks for up to 6 cycles. Patients received subsequent treatment with pembrolizumab and/or chemotherapy. Primary endpoints were objective response rate with cisplatin/nab paclitaxel and safety. Biopsies of a metastatic lesion were collected prior to and at PD on PIKTOR. Whole exome and RNA-sequencing and reverse phase protein arrays (RPPA) were used to phenotype tumors pre- and post-PIKTOR for alterations in DDR, proliferation, and immune response.RESULTS With cisplatin/nab paclitaxel (cis/nab pac) therapy post PIKTOR, 3 patients had clinical benefit (1 partial response (PR) and 2 stable disease (SD) ≥ 6 months) and continued to have durable benefit in progression-free survival with pembrolizumab post-cis/nab pac for 1.2, 2, and 3.6 years. Their post-PIKTOR metastatic tissue displayed decreased mismatch repair (MMR), increased tumor mutation burden, and significantly lower levels of 53BP1, DAG Lipase β, GCN2, AKT Ser473, and PKCzeta Thr410/403 compared to pre-PIKTOR tumor tissue.CONCLUSIONS Priming patients’ chemotherapy-pretreated metastatic TNBC with PIKTOR led to very prolonged response/disease control with subsequent cis/nab pac, followed by pembrolizumab, in 3 of 10 treated patients. Our multi-omics approach revealed a higher number of genomic alterations, reductions in MMR, and alterations in immune and stress response pathways post-PIKTOR in patients who had durable responses.TRIAL REGISTRATION This clinical trial was registered on June 21, 2017, at ClinicalTrials.gov using identifier NCT03193853.

show abstract

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Cited by 38 publications

References 111 publications

Knockdown of TFRC suppressed the progression of nasopharyngeal carcinoma by downregulating the PI3K/Akt/mTOR pathway

Knockdown of TFRC suppressed the progression of nasopharyngeal carcinoma by downregulating the PI3K/Akt/mTOR pathway

MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER+ Breast Cancer

Pilot clinical trial and phenotypic analysis in chemotherapy-pretreated, metastatic triple-negative breast cancer patients treated with oral TAK-228 and TAK-117 (PIKTOR) to increase DNA damage repair deficiency followed by cisplatin and nab paclitaxel

Contact Info

Product

Resources

About