Synergistic interactions with PI3K inhibition that induce apoptosis

Zwang, Yaara; Jonas, Oliver; Chen, Casandra; Rinne, Mikael L.; Doench, John G.; Piccioni, Federica; Li, Tan; Huang, Hai‐Tsang; Wang, Jinhua; Ham, Young Jin; O’Connell, Joyce T.; Bhola, Patrick; Doshi, Mihir B.; Whitman, Matthew A.; Cima, Michael J.; Letaï, Anthony; Root, David E.; Langer, Robert; Gray, Nathanael S.; Hahn, William C.

doi:10.7554/elife.24523

Cited by 25 publications

(18 citation statements)

References 42 publications

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“…We also identify several resistance mechanisms that involve cell cycle proteins, namely, cyclin E and CDK 2 (cycE/CDK2 = ON), p21/p27 (p21/p27 = OFF), E2F (E2F = 3), Rb (pRb = 3), or proteins of the mitochondrial apoptosis pathway, namely BIM (BIM = OFF), BAD (BAD = OFF), MCL1 (MCL1 = ON), and BCL2 (BCL2 = ON). Several of these resistance mechanisms are supported by experimental evidence (Rb, MCL1, and BAD) or consistent with clinical observations (AKT) (46,47,49,53).…”

Section: The Network Model Predicts Mapk Foxo3 Akt Myc and Cell Csupporting

confidence: 66%

“…Tables 1 and 2 ON). Several of these resistance mechanisms are supported by experimental evidence (Rb, MCL1, and BAD) or consistent with clinical observations (AKT) (46,47,49,53).…”

Section: The Network Model Predicts Mapk Foxo3 Akt Myc and Cell Csupporting

confidence: 66%

“…As a result of the development of PI3K inhibitors, there has been an increased interest in investigating the resistance mechanisms to PI3K inhibitors in the context of breast cancer, and several studies have been done in this direction (41)(42)(43)(44)(45)(46)(47)(48)(49). These studies have elucidated several resistance mechanisms to PI3KCA inhibitors such as PIK3CB signaling (an alternative PI3K isoform), HER3 (ERBB3) receptor activity (which is upstream of PI3K, and strongly activates the MAPK and PI3K pathway), mTORC1 signaling (which would otherwise be activated by the PI3K pathway), estrogen receptor (ER) transcriptional regulatory activity (which provides PI3K-independent means of promoting proliferation), , and signaling through the PIM (PIM1, PIM2, and PIM3), SGK (SGK1, SGK2, and SGK3), and PDK1 protein kinases (which act independently of PI3K, and have functions similar to AKT).…”

Section: Resistance Mechanisms To Pi3k Inhibitors In Breast Cancermentioning

confidence: 99%

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A network modeling approach to elucidate drug resistance mechanisms and predict combinatorial drug treatments in breast cancer

Zañudo

Albert

2017

Preprint

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Background: Mechanistic models of within-cell signal transduction networks can explain how these networks integrate internal and external inputs to give rise to the appropriate cellular response. These models can be fruitfully used in cancer cells, whose aberrant decision-making regarding their survival or death, proliferation or quiescence can be connected to errors in the state of nodes or edges of the signal transduction network. Results: Here we present a comprehensive network, and discrete dynamic model, of signal transduction in breast cancer based on the literature of ER+, HER2+, and PIK3CA-mutant breast cancers. The network model recapitulates known resistance mechanisms to PI3K inhibitors and suggests other possibilities for resistance. The model also reveals known and novel combinatorial interventions that are more effective than PI3K inhibition alone. Conclusions: The use of a logic-based, discrete dynamic model enables the identification of results that are mainly due to the organization of the signaling network, and those that also depend on the kinetics of individual events. Network-based models such as this will play an increasing role in the rational design of high-order therapeutic combinations.

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Section: The Network Model Predicts Mapk Foxo3 Akt Myc and Cell Csupporting

confidence: 66%

“…Tables 1 and 2 ON). Several of these resistance mechanisms are supported by experimental evidence (Rb, MCL1, and BAD) or consistent with clinical observations (AKT) (46,47,49,53).…”

Section: The Network Model Predicts Mapk Foxo3 Akt Myc and Cell Csupporting

confidence: 66%

Section: Resistance Mechanisms To Pi3k Inhibitors In Breast Cancermentioning

confidence: 99%

See 1 more Smart Citation

A network modeling approach to elucidate drug resistance mechanisms and predict combinatorial drug treatments in breast cancer

Zañudo

Albert

2017

Preprint

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“…Clinical data of PI3K and mTOR inhibitors have shown only modest benefit in breast cancers, with around 2-4 months improvement in PFS and largely disease stabilization in patients 39,56 . Consistent with these clinical observations, most inhibitors in this class cause only a proliferative arrest in vitro 57 and it has been proposed that combinations that induce apoptosis may be used to enhance responses 58 . We observed strong synergy in most cell lines using MLN8237 and any of the PI3K-pathway inhibitors, particularly in addition to RAD001 treatment where we identified synergy in 85% of cell lines.…”

Section: Discussionmentioning

confidence: 74%

Kinome rewiring reveals AURKA is a molecular barrier to the efficacy of PI3K/mTOR-pathway inhibitors in breast cancer

Donnella

Webber

Levin

et al. 2017

Preprint

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Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest. We hypothesized that dynamic changes in signaling, including adaptation and feedback, limit drug efficacy. Using a quantitative chemoproteomics approach we mapped dynamic changes in the kinome in response to various agents and identified signaling changes that correlate with drug sensitivity. Measurement of dynamics across a panel of breast cancer cell lines identified that maintenance of CDK4 and AURKA activity was associated with drug resistance. We tested whether incomplete inhibition of CDK4 or AURKA was a source of therapy failure and found that inhibition of either was sufficient to sensitize most breast cancer cells to PI3K, AKT, and mTOR inhibitors. In particular, drug combinations including the AURKA inhibitor MLN8237 were highly synergistic and induced apoptosis through enhanced suppression of mTOR signaling to S6 and 4E-BP1 leading to tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of target therapy and indicates that Aurora kinase co-inhibition could unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer.

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“…Members of the transforming acidic coiled-coil (TACC) family of proteins, implicated in centrosome regulation and cancer, are of particular interest in this context [121,122]. Indeed, TACC1, a centrosome-localised microtubule-binding protein, was recently identified as a top hit in a genome-wide shRNA screen for genes that convert PI3K inhibitorinduced cytostasis to cytotoxicity, selectively in PIK3CA-mutant cells [123]. This is in line with data indicating that TACC1 overexpression protects cells from cytostasis induced by PI3K inhibition [124].…”

Section: Impact Of Pi3k On Centrosomes (And Vice Versa)mentioning

confidence: 99%

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

Vanhaesebroeck

Bilanges

Madsen

et al. 2019

Preprint

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Genetic activation of the class I PI3K pathway is very common in cancer. This mostly results from oncogenic mutations in PIK3CA, the gene encoding the ubiquitously expressed PI3Kα catalytic subunit, or from inactivation of the PTEN tumour suppressor, a lipid phosphatase which opposes class I PI3K signalling. The clinical impact of PI3K inhibitors in solid tumours, aimed at dampening cancercell-intrinsic PI3K activity, has thus far been limited. Challenges include poor drug tolerance, incomplete pathway inhibition and pre-existing or inhibitor-induced resistance. The principle of pharmacologically targeting cancer-cell-intrinsic PI3K activity also assumes that all cancer-promoting effects of PI3K activation are reversible, which might not be the case. Emerging evidence suggests that genetic PI3K pathway activation can induce and/or allow cells to tolerate chromosomal instability, which -even if occurring in a low fraction of the cell population -might help to facilitate and/or drive tumour evolution. While it is clear that such genomic events cannot be reverted pharmacologically, a role for PI3K in the regulation of chromosomal instability could be exploited by using PI3K pathway inhibitors to prevent those genomic events from happening and/or reduce the pace at which they are occurring, thereby dampening cancer development or progression. Such an impact might be most effective in tumours with clonal PI3K activation and achievable at lower drug doses than the maximum-tolerated doses of PI3K inhibitors currently used in the clinic.

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Synergistic interactions with PI3K inhibition that induce apoptosis

Cited by 25 publications

References 42 publications

A network modeling approach to elucidate drug resistance mechanisms and predict combinatorial drug treatments in breast cancer

A network modeling approach to elucidate drug resistance mechanisms and predict combinatorial drug treatments in breast cancer

Kinome rewiring reveals AURKA is a molecular barrier to the efficacy of PI3K/mTOR-pathway inhibitors in breast cancer

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

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