PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer

Experimental Therapeutics Program, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Oncogene (Impact Factor: 8.46). 01/2011; 30(22):2547-57. DOI: 10.1038/onc.2010.626
Source: PubMed


There is a strong rationale to therapeutically target the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it is highly deregulated in this disease and it also mediates resistance to anti-HER2 therapies. However, initial studies with rapalogs, allosteric inhibitors of mTORC1, have resulted in limited clinical efficacy probably due to the release of a negative regulatory feedback loop that triggers AKT and ERK signaling. Since activation of AKT occurs via PI3K, we decided to explore whether PI3K inhibitors prevent the activation of these compensatory pathways. Using HER2-overexpressing breast cancer cells as a model, we observed that PI3K inhibitors abolished AKT activation. However, PI3K inhibition resulted in a compensatory activation of the ERK signaling pathway. This enhanced ERK signaling occurred as a result of activation of HER family receptors as evidenced by induction of HER receptors dimerization and phosphorylation, increased expression of HER3 and binding of adaptor molecules to HER2 and HER3. The activation of ERK was prevented with either MEK inhibitors or anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. Combined administration of PI3K inhibitors with either HER2 or MEK inhibitors resulted in decreased proliferation, enhanced cell death and superior anti-tumor activity compared with single agent PI3K inhibitors. Our findings indicate that PI3K inhibition in HER2-overexpressing breast cancer activates a new compensatory pathway that results in ERK dependency. Combined anti-MEK or anti-HER2 therapy with PI3K inhibitors may be required in order to achieve optimal efficacy in HER2-overexpressing breast cancer. This approach warrants clinical evaluation.

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Available from: Yasir H Ibrahim, Oct 06, 2015
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    • "Inhibition of the PI3K/Akt pathway by NVP-BEZ235 activates androgen receptor signaling by relieving feedback inhibition of Her2 kinases [83, 84], thus maintaining tumor cell growth in PTEN-deficient murine prostate cancer models. Similarly, use of NVP-BEZ235 in breast and RCC cells induces feedback regulations to sustain cell survival via ERK- and the FoxO/mTORC2-dependent pathways, respectively [85, 86]. These findings highlight that combination therapies of NVP-BEZ235 with inhibitors that target the respective resistance pathways prevalent in each cellular context should be considered in order to maximize the therapeutic efficacy in the clinic setting. "
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    ABSTRACT: Akt regulates critical cellular processes including cell survival and proliferation, glucose metabolism, cell migration, cancer progression and metastasis through phosphorylation of a variety of downstream targets. The Akt pathway is one of the most prevalently hyperactivated signaling pathways in human cancer, thus, research deciphering molecular mechanisms which underlie the aberrant Akt activation has received enormous attention. The PI3K-dependent Akt serine/threonine phosphorylation by PDK1 and mTORC2 has long been thought to be the primary mechanism accounting for Akt activation. However, this regulation alone does not sufficiently explain how Akt hyperactivation can occur in tumors with normal levels of PI3K/PTEN activity. Mounting evidence demonstrates that aberrant Akt activation can be attributed to other posttranslational modifications, which include tyrosine phosphorylation, O-GlcNAcylation, as well as lysine modifications: ubiquitination, SUMOylation and acetylation. Among them, K63-linked ubiquitination has been shown to be a critical step for Akt signal activation by facilitating its membrane recruitment. Deficiency of E3 ligases responsible for growth factor-induced Akt activation leads to tumor suppression. Therefore, a comprehensive understanding of posttranslational modifications in Akt regulation will offer novel strategies for cancer therapy.
    Cell and Bioscience 10/2014; 4(1):59. DOI:10.1186/2045-3701-4-59 · 3.63 Impact Factor
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    • "Although it has a strong antitumor effect, it is not suitable for clinical application, due to its high toxicity.47,48 In contrast, BEZ-235 has been extensively tested in clinical trials for many types of cancers, and has demonstrated high effectiveness and low toxicity.39,40,49–52 In the present study, we applied BEZ-235 in colon cancer HCT-116 in combination with LDH-5-FU to demonstrate their combination effect. "
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    ABSTRACT: Colon cancer is the third most common cancer and the third largest cause of cancer-related death. Fluorouracil (5-FU) is the front-line chemotherapeutic agent for colon cancer. However, its response rate is less than 60%, even in combination with other chemotherapeutic agents. The side effects of 5-FU also limit its application. Nanoparticles have been used to deliver 5-FU, to increase its effectiveness and reduce side effects. Another common approach for colon cancer treatment is targeted therapy against the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. A recently-invented inhibitor of this pathway, BEZ-235, has been tested in several clinical trials and has shown effectiveness and low side effects. Thus, it is a very promising drug for colon cancer treatment. The combination of these two drugs, especially nanoparticle-packed 5-FU and BEZ-235, has not been studied. In the present study, we demonstrated that nanoparticles of layered double hydroxide (LDH) loaded with 5-FU were more effective than a free drug at inhibiting colon cancer cell growth, and that a combination treatment with BEZ-235 further increased the sensitivity of colon cancer cells to the treatment of LDH-packed 5-FU (LDH-5-FU). BEZ-235 alone can decrease colon cancer HCT-116 cell viability to 46% of the control, and the addition of LDH-5-FU produced a greater effect, reducing cell survival to 8% of the control. Our data indicate that the combination therapy of nanodelivered 5-FU with a PI3K/Akt inhibitor, BEZ-235, may promise a more effective approach for colon cancer treatment.
    International Journal of Nanomedicine 07/2014; 9(1):3403-11. DOI:10.2147/IJN.S61633 · 4.38 Impact Factor
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    • "In breast cancer, HER2 amplification is used to guide the use of trastuzumab, an antibody to HER2, and lapatinib, a dual EGFR and HER2 small molecule targeted agent. Resistance to trastuzumab and lapatinib has been linked to aberrations of the PI3K pathway [3]. PI3K abnormalities including activating mutation of PIK3CA and loss of PTEN are common in breast cancer [3-6]. "
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    ABSTRACT: Background The epidermal growth factor receptor family is expressed in breast cancer, and agents targeting this pathway have single agent effects (e.g. traztuzumab). Development of resistance may be due to the presence of alternative pathways, particularly activation of the PI3K/Akt/MTOR pathway. We have therefore examined the effect of inhibitors of this pathway (ZSTK474 and sirolimus) in combination with the epidermal growth factor (EGFR) inhibitors erlotinib and gefitinib in breast MCF10a isogenic cell lines with EGFR, BRAF, AKT, and PI3K mutations. Results PI3K mutation conferred increased activity of EGFR inhibitors against MCF10a cells in comparison with the parental cell line and other mutations studied. Combination of EGFR inhibitors with either the PI3K inhibitor ZSTK474 or the MTOR inhibitor sirolimus showed increased activity. Conclusions These results are encouraging for the use of combinations targeting the PI3K and EGFR pathway simultaneously.
    BMC Research Notes 06/2014; 7(1):397. DOI:10.1186/1756-0500-7-397
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