Treating cancer with phosphatidylinositol-3-kinase inhibitors: increasing efficacy and overcoming resistance

Paddock, Marcia N.; Field, Seth J.; Cantley, Lewis C.

doi:10.1194/jlr.s092130

Cited by 17 publications

(10 citation statements)

References 34 publications

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“…The Food and Drug Administration–approved PI3K inhibitors are isoform-specific or isoform-selective. However, since these inhibitors target the wild-type enzymes, toxicities are unavoidable and remain a major clinical problem ( 11 – 13 ). Another strategy is to develop inhibitors that are specific for the cancer-associated mutants of PI3K, and there are encouraging signs that this degree of specificity can be reached ( 14 , 15 ).…”

mentioning

confidence: 99%

Nanobodies and chemical cross-links advance the structural and functional analysis of PI3Kα

Hart

Liu

Pan

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Nanobodies and chemical cross-linking were used to gain information on the identity and positions of flexible domains of PI3Kα. The application of chemical cross-linking mass spectrometry (CXMS) facilitated the identification of the p85 domains BH, cSH2, and SH3 as well as their docking positions on the PI3Kα catalytic core. Binding of individual nanobodies to PI3Kα induced activation or inhibition of enzyme activity and caused conformational changes that could be correlated with enzyme function. Binding of nanobody Nb3-126 to the BH domain of p85α substantially improved resolution for parts of the PI3Kα complex, and binding of nanobody Nb3-159 induced a conformation of PI3Kα that is distinct from known PI3Kα structures. The analysis of CXMS data also provided mechanistic insights into the molecular underpinning of the flexibility of PI3Kα.

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mentioning

confidence: 99%

Nanobodies and chemical cross-links advance the structural and functional analysis of PI3Kα

Hart

Liu

Pan

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…In fact, the nutrition regimen of cancer patients with no prior record of hyperinsulinemia per se has been drawing increasing attention, both in general patient care and in the clinical evaluation of PI3K inhibitors. 113 , 114 Therefore, our study, which clearly indicates a reduced efficacy of targeted therapeutics in melanoma cells in the presence of insulin, may stimulate clinical evaluation of how high level of insulin impacts the response to anticancer treatment.…”

Section: Discussionmentioning

confidence: 75%

<p>Insulin Reduces the Efficacy of Vemurafenib and Trametinib in Melanoma Cells</p>

Osrodek¹,

Różański²,

Czyż³

2020

CMAR

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Background: Despite the progress made in the clinical management of metastatic melanoma, a patient's response to treatment cannot be fully predicted, and intrinsic or acquired resistance that is developed in most melanoma patients warrants further research efforts. In addition to genetic factors, microenvironmental input should be considered to explain the diversity of response to treatment among melanoma patients. In this study, we evaluated the impact of insulin on patient-derived BRAF V600E melanoma cells, either untreated or treated with vemurafenib or trametinib, inhibitors of BRAF V600 and MEK1/2, respectively. Methods: Cells were cultured in serum-free conditions, either with or without insulin. The activity of the MAPK/ERK and PI3K/AKT pathways was assessed by Western blotting, cell viability, and percentages of Ki-67-and NGFR-positive cells by flow cytometry. Transcript levels were analyzed using qRT-PCR, and γ-H2AX levels by immunoblotting and confocal microscopy. A luminescence-based assay was used to measure glutathione content. Results: While insulin did not influence the MAPK/ERK pathway activity, it had a strong influence on melanoma cells, in which this pathway was suppressed by either vemurafenib or trametinib. In the presence of insulin, both drugs were much less efficient in 1) inhibiting proliferation and reducing the percentage of Ki-67-positive cells, and 2) inducing apoptosis and phosphorylation of histone H2AX in melanoma cells. Changes induced by vemurafenib and trametinib in glutathione homeostasis and DNA repair gene expression were also attenuated by insulin. Moreover, insulin impaired the combined effects of targeted drugs and doxorubicin in melanoma cells. In addition to insulin-induced PI3K/AKT activity, which was either transient or sustainable depending on the cell line, an insulin-triggered increase in the percentage of cells expressing NGFR, a marker of neural crest stem-like cells, may contribute to the reduced drug efficacy. Conclusion: Our results demonstrate the role of insulin in reducing the efficacy of vemurafenib and trametinib. This needs clinical assessment.

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“…Innate and acquired resistance is the major obstacle to treating cancer patients with isiPI3K [ 51 , 52 , 53 ]. Different molecular paths can lead to isiPI3K resistance, including sustained activation of mTORC1 [ 21 , 54 , 55 ], PDK1/SGK1 [ 56 ], and MYC [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer

Badarni

Prasad

Golden

et al. 2021

Cancers

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Over 50% of human papilloma positive head-and-neck cancer (HNCHPV+) patients harbor genomic-alterations in PIK3CA, leading to hyperactivation of the phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) pathway. Nevertheless, despite PI3K pathway activation in HNCHPV+ tumors, the anti-tumor activities of PI3K pathway inhibitors are moderate, mostly due to the emergence of resistance. Thus, for potent and long-term tumor management, drugs blocking resistance mechanisms should be combined with PI3K inhibitors. Here, we delineate the molecular mechanisms of the acquisition of resistance to two isoform-selective inhibitors of PI3K (isiPI3K), alpelisib (BYL719) and taselisib (GDC0032), in HNCHPV+ cell lines. By comparing the transcriptional landscape of isiPI3K-sensitive tumor cells with that of their corresponding isiPI3K-acquired-resistant tumor cells, we found upregulation of insulin growth factor 2 (IGF2) in the resistant cells. Mechanistically, we show that upon isiPI3K treatment, isiPI3K-sensitive tumor cells upregulate the expression of IGF2 to induce cell proliferation via the activation of the IGF1 receptor (IGF1R). Stimulating tumor cells with recombinant IGF2 limited isiPI3K efficacy and released treated cells from S phase arrest. Knocking-down IGF2 with siRNA, or blocking IGF1R with AEW541, resulted in superior anti-tumor activity of isiPI3K in vitro and ex vivo. In vivo, the combination of isiPI3K and IGF1R inhibitor induced stable disease in mice bearing either tumors generated by the HNCHPV+ UM-SCC47 cell line or HPV+ patient-derived xenografts. These findings indicate that IGF2 and the IGF2/IGF1R pathway may constitute new targets for combination therapies to enhance the efficacy of PI3K inhibitors for the treatment of HNCHPV+.

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Treating cancer with phosphatidylinositol-3-kinase inhibitors: increasing efficacy and overcoming resistance

Cited by 17 publications

References 34 publications

Nanobodies and chemical cross-links advance the structural and functional analysis of PI3Kα

Nanobodies and chemical cross-links advance the structural and functional analysis of PI3Kα

<p>Insulin Reduces the Efficacy of Vemurafenib and Trametinib in Melanoma Cells</p>

IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer

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