Anticipating mechanisms of resistance to PI3K inhibition in breast cancer: a challenge in the era of precision medicine

Leroy, Cédric; Amante, Romain J.; Bentires‐Alj, Mohamed

doi:10.1042/bst20140034

Cited by 10 publications

(10 citation statements)

References 57 publications

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“…Several PI3K inhibitors are in clinical trials for many cancers and early results point to multiple mechanisms by which breast tumors do not respond or develop resistance to PI3K inhibitors [11, 12]. As a result PI3K inhibitors are being evaluated in clinical trials in combination with AKT inhibitors, CDK4/6 inhibitors, MTOR inhibitors, HER2 inhibitors, MEK inhibitors, aromatase inhibitors, enzalutamide, tamoxifen, cisplatin, and paclitaxel, but often at the expense of considerable added toxicity [13–16]. GDC-0941 (potent inhibitor of PI3Kα/δ (IC50 3nM) with some activity for β and γ isoforms (IC50 33 and 75nM) ) from Genentech is in phase II clinical trials [17] [18] in combination with endocrine therapy, paclitaxel/docetaxel; BLY719, a selective PI3Kα inhibitor from Novartis (IC50 of 5nM) in combination with the CDK4/6 inhibitor LEE011 is in phase 1b/II trials in ER+ HER2- metastatic breast cancer.…”

Section: Introductionmentioning

confidence: 99%

PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses

Sai

Owens

Novitskiy

et al. 2017

Clinical Cancer Research

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Purpose Metastatic breast cancers continue to elude current therapeutic strategies, including those utilizing PI3K inhibitors. Given the prominent role of PI3Kα,β in tumor growth and PI3Kγ,δ in immune cell function, we sought to determine whether PI3K inhibition altered anti-tumor immunity. Experimental Design The effect of PI3K inhibition on tumor growth, metastasis, and anti-tumor immune response was characterized in mouse models utilizing orthotopic implants of 4T1 or PyMT mammary tumors into syngeneic or PI3Kγ null mice, and patient-derived breast cancer xenografts in humanized mice. Tumor infiltrating leukocytes were characterized by IHC and FACS analysis in BKM120 (30mg/kg, QD) or vehicle treated mice and PI3Kγnull versus PI3KγWT mice. Based on the finding that PI3K inhibition resulted in a more inflammatory tumor leukocyte infiltrate, the therapeutic efficacy of BKM120 (30mg/kg, QD) and anti-PD1 (100µg, twice weekly) was evaluated in PyMT tumor bearing mice. Results Our findings show that PI3K activity facilitates tumor growth and surprisingly, restrains tumor immune surveillance. These activities could be partially suppressed by BKM120 or by genetic deletion of PI3Kγ in the host. The anti-tumor effect of PI3Kγ loss in host, but not tumor, was partially reversed by CD8+T cell depletion. Treatment with therapeutic doses of both BKM120 and antibody to PD-1 resulted in consistent inhibition of tumor growth compared to either agent alone. Conclusions PI3K inhibition slows tumor growth, enhances anti-tumor immunity, and heightens susceptibility to immune checkpoint inhibitors. We propose that combining PI3K inhibition with anti-PD1 may be a viable therapeutic approach for triple negative breast cancer.

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Section: Introductionmentioning

confidence: 99%

PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses

Sai

Owens

Novitskiy

et al. 2017

Clinical Cancer Research

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“…The PI3K pathway is one of the most attractive therapeutic targets and numerous inhibitors are being evaluated in clinical trials [ 8 ]. Pan-PI3K inhibitors are often used at a dose that does not completely block PI3K activity, which may not result in acceptable efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…Although a broad range of PI3K inhibitors are currently in clinical trials, the responses to these compounds as single agents are less robust than expected. Isoform-selective PI3K inhibitors are highly specific and thus can be used at higher concentrations than pan-PI3K inhibitors, resulting in a more robust target inhibition, while limiting side-effect complication [ 8 ]. However, the combination of isoform-selective PI3K inhibitors with additional agents may require the use of lower concentrations to avoid potential toxicities.…”

Section: Introductionmentioning

confidence: 99%

Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition

et al. 2016

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BackgroundThe PI3K pathway is hyperactivated in many cancers, including 70 % of breast cancers. Pan- and isoform-specific inhibitors of the PI3K pathway are currently being evaluated in clinical trials. However, the clinical responses to PI3K inhibitors when used as single agents are not as efficient as expected.MethodsIn order to anticipate potential molecular mechanisms of resistance to the p110α isoform-selective inhibitor BYL719, we developed resistant breast cancer cell lines, assessed the concomitant changes in cellular signaling pathways using unbiased phosphotyrosine proteomics and characterized the mechanism of resistance using pharmacological inhibitors.ResultsWe found an increase in IGF1R, IRS1/IRS2 and p85 phosphorylation in the resistant lines. Co-immunoprecipitation experiments identified an IGF1R/IRS/p85/p110β complex that causes the activation of AKT/mTOR/S6K and stifles the effects of BYL719. Pharmacological inhibition of members of this complex reduced mTOR/S6K activation and restored sensitivity to BYL719.ConclusionOur study demonstrates that the IGF1R/p110β/AKT/mTOR axis confers resistance to BYL719 in PIK3CA mutant breast cancers. This provides a rationale for the combined targeting of p110α with IGF1R or p110β in patients with breast tumors harboring PIK3CA mutations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0697-1) contains supplementary material, which is available to authorized users.

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“…Given this, many studies have been carried out to develop agents inhibiting PI3K-AKT for cancer treatment (3,5,(9)(10)(11)(12). Unfortunately, the existing drugs targeting the PI3K-AKT pathway often result in the development of drug resistance (13), through unknown mechanisms. More studies are therefore necessary to discern the molecular network of PI3K in breast cancer development and progression to design more efficient strategies for the treatment of PI3Kinvolved breast cancer.…”

Section: Introductionmentioning

confidence: 99%

PI3K Positively Regulates YAP and TAZ in Mammary Tumorigenesis Through Multiple Signaling Pathways

Zhao

Montminy

Azad

et al. 2018

Molecular Cancer Research

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Breast cancer is a leading cause of death in women worldwide. Active mutations of PI3K catalytic subunit PIK3CA (e.g., H1047R) and amplification of its homolog PIK3CB are observed in a large number of breast cancers. In recent years, aberrant activation of Transcriptional coactivator with PDZ binding motif (TAZ) and its paralog Yes-associated protein (YAP) have also been found to be important for breast cancer development and progression. However, whether PI3K interacts with YAP/TAZ during mammary tumorigenesis is unknown. Through a systematic gain-of-function screen for kinases involved in mammary tumorigenesis, we identified PIK3CB as a transformation-inducing kinase in breast cells. We further determined that PIK3CB positively regulates YAP and TAZ to promote transformation and inhibit mammary cell death PIK3CB coexpression with TAZ, rather than PIK3CB or TAZ alone, in human MCF10A nontumorigenic mammary cells is sufficient for tumor formation in mice Interestingly, we also determined that PIK3CA-H1047R enhances YAP and TAZ activity in mammary tumorigenesis Mechanistically, the regulation of YAP/TAZ by both PIK3CA and PIK3CB occurs through multiple signaling pathways including LATS-dependent and LATS-independent pathways. Therefore, in this study, we determine that PI3K and YAP/TAZ interact to promote breast cancer cell transformation. This study provides the first evidence that the Hippo pathway effectors TAZ and YAP are critical mediators of PI3K-induced mammary tumorigenesis and synergistically function together with PI3K in transformation of mammary cells. These findings may provide a novel rationale for targeting YAP/TAZ alone or in combination with PI3K inhibitors for breast cancer therapy in the future. .

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Anticipating mechanisms of resistance to PI3K inhibition in breast cancer: a challenge in the era of precision medicine

Cited by 10 publications

References 57 publications

PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses

PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses

Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition

PI3K Positively Regulates YAP and TAZ in Mammary Tumorigenesis Through Multiple Signaling Pathways

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