Inhibiting the PI3K signaling pathway: buparlisib as a new targeted option in breast carcinoma

Estevez, LG; García, Elena; Hidalgo, Manuel

doi:10.1007/s12094-015-1410-z

Cited by 9 publications

(11 citation statements)

References 60 publications

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“…Genomic alterations in PIK3CA , the gene encoding the catalytic subunit of PI3K, are common in ER+ tumors [28 ● ,29,30]. It is thought that suppression of the PI3K/AKT/mTOR pathway can lead to increased activity of ER, facilitating resistance, and therefore many groups have used preclinical models to elucidate the mechanisms of PI3K/AKT/mTOR pathway inhibitors and the influence these compounds have on estrogen-mediated signaling [19 ● ,21 ●● ,25,31–33]. …”

Section: Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors

Mills

Rutkovsky

Giordano

2018

Current Opinion in Pharmacology

120

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Several mechanisms of resistance have been identified, underscoring the complex nature of estrogen receptor (ER) signaling and the many connections between this pathway and other essential signaling pathways in breast cancer cells. Many therapeutic targets of cell signaling and cell cycle pathways have met success with endocrine therapy and remain an ongoing area of investigation. This review focuses on two major pathways that have recently emerged as important opportunities for therapeutic intervention in endocrine resistant breast tumors: PI3K/AKT/mTOR cell signaling and cyclinD1/cyclin-dependent kinase 4/6 cell cycle pathways. Additionally, we highlight individual and combination strategies in current clinical trials that target these pathways and others under investigation for the treatment of ER positive breast cancer.

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Section: Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors

Mills

Rutkovsky

Giordano

2018

Current Opinion in Pharmacology

120

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“…The third pathway analyzed in our study was the PI3K pathway, which was found altered in 139 (56.3%) cases. It is reported that alteration of the PI3K pathway is mainly observed in HR‐positive diseases . The highest alteration rate of the PI3K pathway was found in HR+HER2− breast cancers (Table ).…”

Section: Discussionmentioning

confidence: 95%

“…It is reported that alteration of the PI3K pathway is mainly observed in HR-positive diseases. 47 The highest alteration rate of the PI3K pathway was found in HR+HER2− breast cancers (Table S2). In addition, aberrant activation of the PI3K pathway is related to resistance to endocrine therapy and chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Somatic alterations of TP53, ERBB2, PIK3CA and CCND1 are associated with chemosensitivity for breast cancers

Yang

Bao

et al. 2019

Cancer Science

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The correlation of genetic alterations with response to neoadjuvant chemotherapy (NAC) has not been fully revealed. In this study, we enrolled 247 breast cancer patients receiving anthracycline‐taxane‐based NAC treatment. A next generation sequencing (NGS) panel containing 36 hotspot breast cancer‐related genes was used in this study. Two different standards for the extent of pathologic complete response (pCR), ypT0/isypN0 and ypT0/is, were used as indicators for NAC treatment. TP53 mutation (n = 149, 60.3%), PIK3CA mutation (n = 109, 44.1%) and MYC amplification (n = 95, 38.5%) were frequently detected in enrolled cases. TP53 mutation ( P = 0.019 for ypT0/isypN0 and P = 0.003 for ypT0/is) and ERBB2 amplification ( P < 0.001 for both ypT0/isypN0 and ypT0/is) were related to higher pCR rates. PIK3CA mutation ( P = 0.040 for ypT0/isypN0) and CCND2 amplification ( P = 0.042 for ypT0/is) showed reduced sensitivity to NAC. Patients with MAPK pathway alteration had low pCR rates ( P = 0.043 for ypT0/is). Patients with TP53 mutation (−) PIK3CA mutation (−) ERBB2 amplification (+) CCND1 amplification (−), TP53 mutation (+) PIK3CA mutation (−) ERBB2 amplification (+) CCND1 amplification (−) or TP53 mutation (+) PIK3CA mutation (+) ERBB2 amplification (+) CCND1 amplification (−)had significantly higher pCR rates ( P < 0.05 for ypT0/isypN0 and ypT0/is) than wild type genotype tumors. Some cancer genetic alterations as well as pathway alterations were associated with chemosensitivity to NAC treatment. Our study may shed light on the molecular characteristics of breast cancer for prediction of NAC expectations when breast cancer is first diagnosed by biopsy.

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“…PI3K phosphorylates phosphatidylinositol 4,5 biphosphate (PIP2) to phosphatidylinositol 3,4,5 triphosphate (PIP3) and later the accumulation of PIP3 at the membrane leads to the recruitment of AKT and its following phosphorylation by PDK1 and mTORC2. [6,7,8] Some of the paths by which activated AKT promotes cell growth, and survival are:…”

Section: Treatment In Endocrine Therapy-resistant Casesmentioning

confidence: 99%

“…Buparlisib is also the subject of a phase II trial of paclitaxel combined with trastuzumab in HER2-overexpressing BC (NCT01816594). [5,8,24] The use of isoform-specific PIs is just one of the approaches to attain notable pathway suppression clinically with favorable adverse effect outline. Every isoform has a is involved in a specific way in normal physiological processes and disease.…”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

Hormone Therapy in Advanced Er+/Her2- Negative Breast Cancer With Pi3k Inhibitors: A Review of the Literature

Inkov¹,

Penkova²,

Baytchev³

et al. 2016

IJSM

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Breast cancer is a heterogenous disease, showing as several different clinical and histologic types. Most of breast cancers express hormone receptors for estrogen and progesterone, which are considered as estrogen receptor-positive and progesterone-receptor-positive, respectively. Endocrine therapy was the first class of target-directed therapy approved for treating breast cancer and is still very important for the treatment of HR+ breast cancer because of its effectiveness and good toxicity profile. It targets receptormediated signaling pathways implicated in cell survival and proliferation, such as those mediated by hormone receptors. Although these approaches have improved the management of advanced breast cancer, many patients either fail to respond to initial therapy (primary or de novo resistance) or eventually become resistant to treatment (secondary or acquired resistance). To expand the use of existing endocrine treatments and their efficiency, new methods are needed. Such new approaches would boost the benefit of existing endocrine therapy by extending time to disease progression, avoiding or overcoming resistance to endocrine treatment, and delaying the use of chemotherapy. This article will review the central role of the PI3K inhibitors in driving ER+/HER2-breast tumors. Also, schemes to combine pathway inhibitors with endocrine therapy for better patient outcome, and approaches to identify patient populations that would benefit most from inhibition of the PI3K/AKT/mTOR pathway will be assessed.

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Inhibiting the PI3K signaling pathway: buparlisib as a new targeted option in breast carcinoma

Cited by 9 publications

References 60 publications

Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors

Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors

Somatic alterations of TP53, ERBB2, PIK3CA and CCND1 are associated with chemosensitivity for breast cancers

Hormone Therapy in Advanced Er+/Her2- Negative Breast Cancer With Pi3k Inhibitors: A Review of the Literature

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