Rationale-based therapeutic combinations with PI3K inhibitors in cancer treatment

Castel, Pau; Toska, Eneda; Zumsteg, Zachary S.; Carmona, Francesc; Elkabets, Moshe; Bosch, Ana; Scaltriti, Maurizio

doi:10.4161/23723548.2014.963447

Cited by 9 publications

(11 citation statements)

References 173 publications

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“…ARQ 092 and ARQ 087 are being tested in clinical trials as single agents (NCT01473095, NCT01752920), with encouraging signs of efficacy in different cancer types. An increasingly common strategy in cancer treatment involves the combination of agents targeting different pathways or targeting the same pathway at multiple points 26 , 27 , and as recently shown by Davies et al 30 in endometrial and bladder tumors, there is a preclinical and clinical rationale for combining AKT and FGFR inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, in the cancer cell lines with genetically altered FGFR2, concomitant inhibition of FGFR and mTORC1 performed better in terms of antiproliferation and antitumor activity compared with single agents 24 , 25 . Clinical studies have been undertaken to evaluate the effect of PI3K/AKT pathway inhibitors in combination with estrogen antagonists, aromatase inhibitors, and HER2 inhibitors 26 , 27 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In-vitro and in-vivo combined effect of ARQ 092, an AKT inhibitor, with ARQ 087, a FGFR inhibitor

Hall

Eathiraj

et al. 2017

Anti-Cancer Drugs

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In-vitro and in-vivo combined effect of ARQ 092, an AKT inhibitor, with ARQ 087, a FGFR inhibitor

Hall

Eathiraj

et al. 2017

Anti-Cancer Drugs

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“…High levels of DNA-PKcs were correlated with poor prognosis as well as an increased risk of recurrence and metastasis in patients with OS. Furthermore, the expression of this catalytic subunit was increased in MG63 cells treated with cisplatin and etoposide [78] ; the expression of DNA-PKcs in cisplatin-resistant MG-63 OS cells appears to be regulated by MARK2 via the PI3K/AKT/mTOR pathway. In this pathway, the protein most strongly associated with DNA damage repair is AKT; it has been reported that DNA damage activates AKT.…”

Section: Pi3k Mechanistic Target Of Rapamycin Akt and Microtubule Aff...mentioning

confidence: 95%

“…In this pathway, the protein most strongly associated with DNA damage repair is AKT; it has been reported that DNA damage activates AKT. In addition, it appears that AKT phosphorylation on S473 is dependent on DNA-PK; AKT1 forms a complex with DNA-PKcs, resulting in the activation and auto-phosphorylation of the S2056 of DNA-PKcs [ 79 ] . Another important protein is mTOR, a key regulator of the PI3K/AKT pathway; overactivation of mTOR is associated with resistance to cisplatin.…”

Section: Signal Transduction Pathwaysmentioning

confidence: 99%

An overview of resistance to chemotherapy in osteosarcoma and future perspectives

García-Ortega¹,

Cabrera-Nieto²,

Caro-Sánchez³

et al. 2022

Cancer Drug Resist

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Osteosarcoma (OS) is the most common type of bone sarcoma. Despite the availability of multimodal treatment with surgery and chemotherapy, the clinical results remain unsatisfactory. The main reason for the poor outcomes in patients with OS is the development of resistance to methotrexate, cisplatin, doxorubicin, and ifosfamide. Molecular and cellular mechanisms associated with resistance to chemotherapy include DNA repair and cell-cycle alterations, enhanced drug efflux, increased detoxification, resistance to apoptosis, autophagy, tumor extracellular matrix, and angiogenesis. This versatility of cells to generate chemoresistance has motivated the use of anti-angiogenic therapy based on tyrosine kinase inhibitors. This approach has shown that other therapies, along with standard chemotherapy, can improve responses to therapy in patients with OS. Moreover, microRNAs may act as predictors of drug resistance in OS. This review provides insight into the molecular and cellular mechanisms involved in the development of resistance during the treatment of OS and discusses promising novel therapies (e.g., afatinib and palbociclib) for overcoming resistance to chemotherapy in OS.

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“…PI3Ks are the vital regulators of apoptosis and cellular functions involve in cancers . In the cancer treatment as well as in drug development, molecular analysis of small molecule entities with PI3K inhibition plays an important role ; . PI3K being the signal transducer enzymes and highly involved in the phosphorylation of the inositol ring of phosphatidylinositol (PtdIns) at 3‐position hydroxyl group .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Substituted Quinolinyl Ether‐based Inhibitors of PI3K as Potential Anticancer Agents

Aggile

Mundre

Napoleon

2018

Journal of Heterocyclic Chem

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A new strategy for the preparation of 8-quinolyl ethers 3(a-g), 5(a-g), and 7(a-d) was studied by copper (II)-catalyzed methodology in the presence of Cs 2 CO 3 and acetone-water mixture (1:1). Screening of quinolinyl-8-ethers was investigated against anticancer expressive studies to validate new chemical entity in medicinal chemistry. Approaches were evaluated against breast cancer (MCF-7), skin cancer (G-361), and colon cancer (HCT 116) cell lines. Inhibitory potentials against phosphoinositide-3-kinase (PI3K) enzyme responsible for cancer development have been evaluated by competitive ELISA studies. In PI3K assay, 3a-c were inactive (IC 50 > 5 μM), while 3e-g, 5a, 5c-e, 5g, 7a, and 7d showed a moderate activity (IC 50 ≥ 0.05 μM). Compounds (5b, 5f, 7b, and 7c) showed significant activity (IC 50 < 1.0 μM); thus, their anticancer activities were carried out. Anticancer activity was found to be selective towards breast cancer (MCF-7); 5b, 5f, 7b, and 7c showed predominant relative percentage activities of 74.12%, 79.04%, 72.56%, and 78.47%, with IC 50 values of 5b (2.27 ± 0.88 μM), 5f (1.38 ± 0.60 μM), 7b (2.64 ± 0.86 μM), and 7c (1.87 ± 0.68 μM) compared with the standard doxorubicin 73.14% inhibition (IC 50 = 1.98 ± 0.75 μM). Docking study also conducted to find out the binding interactions with p110α (PDB ID: 3T8M) enzyme. Compounds 5b, 5f, 7b, and 7c showed best docking score into the active site of PI3K 12.59, 10.51, 56.52, and 8.61 nM. Structure-activity relationship studies demonstrated that the synthesized compounds are the potential PI3K inhibitors to treat various cancer-related diseases.

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Rationale-based therapeutic combinations with PI3K inhibitors in cancer treatment

Cited by 9 publications

References 173 publications

In-vitro and in-vivo combined effect of ARQ 092, an AKT inhibitor, with ARQ 087, a FGFR inhibitor

In-vitro and in-vivo combined effect of ARQ 092, an AKT inhibitor, with ARQ 087, a FGFR inhibitor

An overview of resistance to chemotherapy in osteosarcoma and future perspectives

Synthesis of Substituted Quinolinyl Ether‐based Inhibitors of PI3K as Potential Anticancer Agents

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