Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells

Muranen, Taru; Selfors, Laura M.; Worster, Devin; Iwanicki, Marcin P.; Song, Loling; Morales, Fabiana C.; Gao, Shumin; Mills, Gordon B.; Brugge, Joan S.

doi:10.1016/j.ccr.2011.12.024

Cited by 352 publications

(344 citation statements)

References 78 publications

(102 reference statements)

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“…4C). Our data are therefore consistent with published studies showing that kinase signaling is remodeled in response to chronic kinase inhibition (27,33). Because of the depth of our analyses, however, our data emphasize the extent to which signaling networks are modulated as a whole to overcome chronic inhibition of single nodes.…”

Section: Discussionsupporting

confidence: 82%

Empirical inference of circuitry and plasticity in a kinase signaling network

Wilkes

Terfve

Gribben

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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Our understanding of physiology and disease is hampered by the difficulty of measuring the circuitry and plasticity of signaling networks that regulate cell biology, and how these relate to phenotypes. Here, using mass spectrometry-based phosphoproteomics, we systematically characterized the topology of a network comprising the PI3K/Akt/mTOR and MEK/ERK signaling axes and confirmed its biological relevance by assessing its dynamics upon EGF and IGF1 stimulation. Measuring the activity of this network in models of acquired drug resistance revealed that cells chronically treated with PI3K or mTORC1/2 inhibitors differed in the way their networks were remodeled. Unexpectedly, we also observed a degree of heterogeneity in the network state between cells resistant to the same inhibitor, indicating that even identical and carefully controlled experimental conditions can give rise to the evolution of distinct kinase network statuses. These data suggest that the initial conditions of the system do not necessarily determine the mechanism by which cancer cells become resistant to PI3K/mTOR targeted therapies. The patterns of signaling network activity observed in the resistant cells mirrored the patterns of response to several drug combination treatments, suggesting that the activity of the defined signaling network truly reflected the evolved phenotypic diversity.signaling network | phosphoproteomics | systems biology | PI3K | MEK

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Section: Discussionsupporting

confidence: 82%

Empirical inference of circuitry and plasticity in a kinase signaling network

Wilkes

Terfve

Gribben

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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“…In fact, whereas GDC-0941 treatment results in inhibition of both ERK and AKT activation, RAS activity was modestly increased. Although more studies are needed to elucidate the feedback mechanism leading from PI3K inhibition to RAS activation, it is possible that PI3K/AKT inhibition releases a negative feedback on receptor tyrosine kinases (RTKs) that, in turn, stimulate RAS (11,14,22,23). Additionally, other regulators of RAS activation may be regulated by PI3K, such as a RAS-GAP that contains a PH domain (24).…”

Section: Discussionmentioning

confidence: 99%

PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1

Ebi

Costa

Faber

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

178

163

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The PI3K pathway is genetically altered in excess of 70% of breast cancers, largely through PIK3CA mutation and HER2 amplification. Preclinical studies have suggested that these subsets of breast cancers are particularly sensitive to PI3K inhibitors; however, the reasons for this heightened sensitivity are mainly unknown. We investigated the signaling effects of PI3K inhibition in PIK3CA mutant and HER2 amplified breast cancers using PI3K inhibitors currently in clinical trials. Unexpectedly, we found that in PIK3CA mutant and HER2 amplified breast cancers sensitive to PI3K inhibitors, PI3K inhibition led to a rapid suppression of Rac1/p21-activated kinase (PAK)/protein kinase C-RAF (C-RAF)/ protein kinase MEK (MEK)/ERK signaling that did not involve RAS. Furthermore, PI3K inhibition led to an ERK-dependent up-regulation of the proapoptotic protein, BIM, followed by induction of apoptosis. Expression of a constitutively active form of Rac1 in these breast cancer models blocked PI3Ki-induced down-regulation of ERK phosphorylation, apoptosis, and mitigated PI3K inhibitor sensitivity in vivo. In contrast, protein kinase AKT inhibitors failed to block MEK/ERK signaling, did not upregulate BIM, and failed to induce apoptosis. Finally, we identified phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) as the PI(3,4,5)P3-dependent guanine exchange factor for Rac1 responsible for regulation of the Rac1/C-RAF/MEK/ERK pathway in these cells. The expression level of P-Rex1 correlates with sensitivity to PI3K inhibitors in these breast cancer cell lines. Thus, PI3K inhibitors have enhanced activity in PIK3CA mutant and HER2 amplified breast cancers in which PI3K inhibition down-regulates both the AKT and Rac1/ERK pathways. In addition, P-Rex1 may serve as a biomarker to predict response to single-agent PI3K inhibitors within this subset of breast cancers.

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“…There is considerable preclinical evidence supporting this approach, for example, in the setting of combining inhibitors of mitogen-activated protein (MAP)-extracellular signal-regulated kinase (ERK) kinase (MEK; MAP kinase kinase, MAP2K) with inhibitors of PI3 kinase (phosphatidylinositol 3-kinase, PIK3CA) or (2-7) BRAF (8)(9)(10), and these combinations are beginning to show efficacy in the clinic (11). A third approach to enhancing the efficacy of targeted therapy is to simultaneously target downstream proteins that protect tumor cells from apoptosis and thus increase overall cell killing (12)(13)(14). This strategy relies on increasing cancer cell cytotoxicity cells to decrease the probability that a cell will survive to develop resistance.…”

Section: Introductionmentioning

confidence: 99%

Bcl-2/Bcl-xL Inhibition Increases the Efficacy of MEK Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models

Tan¹,

Wong²,

Nannini³

et al. 2013

Molecular Cancer Therapeutics

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Although mitogen-activated protein (MAP)-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition is predicted to cause cell death by stabilization of the proapoptotic BH3-only protein BIM, the induction of apoptosis is often modest. To determine if addition of a Bcl-2 family inhibitor could increase the efficacy of a MEK inhibitor, we evaluated a panel of 53 non-small cell lung cancer and pancreatic cancer cell lines with the combination of navitoclax (ABT-263), a Bcl-2/Bcl-x L (BCL2/BCL2L1) antagonist, and a novel MAP kinase (MEK) inhibitor, G-963. The combination is synergistic in the majority of lines, with an enrichment of cell lines harboring KRAS mutations in the high synergy group. Cells exposed to G-963 arrest in G 1 and a small fraction undergo apoptosis. The addition of navitoclax to G-963 does not alter the kinetics of cell-cycle arrest, but greatly increases the percentage of cells that undergo apoptosis. The G-963/navitoclax combination was more effective than either single agent in the KRAS mutant H2122 xenograft model; BIM stabilization and PARP cleavage were observed in tumors, consistent with the mechanism of action observed in cell culture.

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Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells

Cited by 352 publications

References 78 publications

Empirical inference of circuitry and plasticity in a kinase signaling network

Empirical inference of circuitry and plasticity in a kinase signaling network

PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1

Bcl-2/Bcl-xL Inhibition Increases the Efficacy of MEK Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models

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