A chemical-genetic screen reveals a mechanism of resistance to PI3K inhibitors in cancer

Muellner, Markus K.; Uras, Iris Z.; Gapp, Bianca V.; Kerzendorfer, Claudia; Šmída, Michal; Lechtermann, Hannelore; Craig-Mueller, Nils; Colinge, Jacques; Duernberger, Gerhard; Nijman, Sebastian M.

doi:10.1038/nchembio.695

Cited by 157 publications

(133 citation statements)

References 44 publications

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“…For example, NVP-BEZ235 upregulates ER expression in ER-positive luminal B subtype of breast carcinomas (34). Long-term NVP-BEZ235 treatment also stimulates MYC expression and leads to drug resistance in breast cancers (25,26).…”

Section: Discussionmentioning

confidence: 99%

“…The transcription of MYC is promoted by AR in prostate cancers, whereas AR suppresses MYC expression in female breast carcinomas (23,24). Recent studies show that long-term NVP-BEZ235 treatment upregulates MYC expression in breast cancer cells, leading to NVP-BEZ235 resistance (25,26). Therefore, we postulated that the presence of DHT during NVP-BEZ235 treatment could effectively block NVP-BEZ235-induced MYC upregulation in breast cancers.…”

Section: Armentioning

confidence: 99%

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Activation of AR Sensitizes Breast Carcinomas to NVP-BEZ235's Therapeutic Effect Mediated by PTEN and KLLN Upregulation

Wang

et al. 2014

Molecular Cancer Therapeutics

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NVP-BEZ235 is a newly developed dual PI3K/mTOR inhibitor, being tested in multiple clinical trials, including breast cancer. NVP-BEZ235 selectively induces cell growth inhibition in a subset, but not all, breast cancer cell lines. However, it remains a challenge to distinguish between sensitive and resistant tumors, particularly in the pretreatment setting. Here, we used ten breast cancer cell lines to compare NVP-BEZ235 sensitivity and in the context of androgen receptor (AR) activation during NVP-BEZ235 treatment. We also used female SCID mice bearing breast tumor xenografts to investigate the beneficial effect of dihydrotestosterone/NVP-BEZ235 combination treatment compared with each alone. We found that AR-positive breast cancer cell lines are much more sensitive to NVP-BEZ235 compared with AR-negative cells, regardless of PTEN or PI3KCA status. Reintroducing AR expression in NVP-BEZ235 nonresponsive AR-negative cells restored the response. DHT/NVP-BEZ235 combination not only resulted in a more significant growth inhibition than either drug alone, but also achieved tumor regression and complete responses for AR þ /ER þ tumors. This beneficial effect was mediated by dihydrotestosterone (DHT)-induced PTEN and KLLN expression. Furthermore, DHT could also reverse NVP-BEZ235-induced side effects such as skin rash and weight loss. Our data suggest that AR expression may be an independent predictive biomarker for response to NVP-BEZ235. AR induction could add benefit during NVP-BEZ235 treatment in patients, especially with AR þ

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Section: Discussionmentioning

confidence: 99%

Section: Armentioning

confidence: 99%

Activation of AR Sensitizes Breast Carcinomas to NVP-BEZ235's Therapeutic Effect Mediated by PTEN and KLLN Upregulation

Wang

et al. 2014

Molecular Cancer Therapeutics

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“…The combination of PI3K inhibitors with MEK or RSK inhibitors may help overcome this resistance [Janku et al 2011[Janku et al , 2012Muellner et al 2011;Serra et al 2013]. KRAS mutations also lead to resistance to PI3K/mTOR inhibitors since they seem to bypass the PI3K pathway [Ihle et al 2009;Di Nicolantonio et al 2010;Janku et al 2011].…”

Section: Biomarkers Of Resistancementioning

confidence: 99%

The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers

2014

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Abstract:The phosphoinositide 3 kinase (PI3K)/Akt/mammalian (or mechanistic) target of rapamycin (mTOR) pathway is a complicated intracellular pathway, which leads to cell growth and tumor proliferation and plays a significant role in endocrine resistance in breast cancer. Multiple compounds targeting this pathway are being evaluated in clinical trials. These agents are generally well tolerated and can be used in combination with targeted therapies, endocrine therapy or cytotoxic agents. The identification of subtypes of tumors more likely to respond to these therapeutics cannot be overemphasized, since breast cancer is a very heterogeneous malignancy. Activation of pathways such as KRAS and MEK can act as escape mechanisms that lead to resistance, thus a combination of agents targeting multiple steps of the intracellular machinery is promising. There is evidence that tumors with PIK3CA mutations are more sensitive to inhibitors of the PI3K pathway but this has yet to be validated. Large clinical trials with correlative studies are necessary to identify reliable biomarkers of efficacy.

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“…Recently, two studies suggested the involvement of the MYC oncogene, which is downstream of the PI3K/mTOR pathway [31]. First, an unbiased screen showed that MYC conferred resistance to BEZ235 in the human mammary epithelial cell (HMEC) line MCF-10A, and that BEZ235-resistant human cell lines had higher c-MYC gene copy number compared to their sensitive counterparts [32]. Second, MYC and eIF4E amplification was identified in BEZ235-resistant HMECs in addition to genome-wide copy number alteration [33].…”

Section: + Bez235 In Vivomentioning

confidence: 99%

Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors

et al. 2014

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Combinatorial targeted therapies are more effective in treating cancer by blocking by-pass mechanisms or inducing synthetic lethality. However, their clinical application is hampered by resistance and toxicity. To meet this important challenge, we developed and tested a novel concept of biomarker-guided sequential applications of various targeted therapies using ErbB2-overexpressing/PTEN-low, highly aggressive breast cancer as our model. Strikingly, sustained activation of ErbB2 and downstream pathways drives trastuzumab resistance in both PTEN-low/ trastuzumab-resistant breast cancers from patients and mammary tumors with intratumoral heterogeneity from genetically-engineered mice. Although lapatinib initially inhibited trastuzumab-resistant mouse tumors, tumors bypassed the inhibition by activating the PI3K/mTOR signaling network as shown by the quantitative protein arrays. Interestingly, activation of the mTOR pathway was also observed in neoadjuvant lapatinib-treated patients manifesting lapatinib resistance. Trastuzumab + lapatinib resistance was effectively overcome by sequential application of a PI3K/mTOR dual kinase inhibitor (BEZ235) with no significant toxicity. However, our p-RTK array analysis demonstrated that BEZ235 treatment led to increased ErbB2 expression and phosphorylation in genetically-engineered mouse tumors and in 3-D, but not 2-D, culture, leading to BEZ235 resistance. Mechanistically, we identified ErbB2 protein stabilization and activation as a novel mechanism of BEZ235 resistance, which was reversed by subsequent treatment with lapatinib + BEZ235 combination. Remarkably, this sequential application of targeted therapies guided by biomarker changes in the tumors rapidly evolving resistance doubled the life-span of mice bearing exceedingly aggressive tumors. This fundamentally novel approach of using targeted therapies in a sequential order can effectively target and reprogram the signaling networks in cancers evolving resistance during treatment.

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A chemical-genetic screen reveals a mechanism of resistance to PI3K inhibitors in cancer

Cited by 157 publications

References 44 publications

Activation of AR Sensitizes Breast Carcinomas to NVP-BEZ235's Therapeutic Effect Mediated by PTEN and KLLN Upregulation

Activation of AR Sensitizes Breast Carcinomas to NVP-BEZ235's Therapeutic Effect Mediated by PTEN and KLLN Upregulation

The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers

Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors

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