Assessment of the <i>In Vivo</i> Activity of PI3K and MEK Inhibitors in Genetically Defined Models of Colorectal Cancer

Raja, Meera; Zverev, Matt; Seipel, Katja; Williams, Gareth; Clarke, Alan Richard; Shaw, Paul

doi:10.1158/1535-7163.mct-15-0223

Cited by 14 publications

(10 citation statements)

References 35 publications

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“…Our validation of this phenomenon with spheroids of KRAS-mutant HCT116 cells indicates that MEKi-induced activation of PI3K/AKT/mTOR pathway is a major mechanism of feedback signaling in colorectal cancer cells that we have studied. Our results are consistent with other reports that showed phosphorylation of AKT in various RAF- and RAS-mutant lung and colorectal cancer cells under RAFi or MEKi treatments [45], [46], and in a genetically engineered Apc- and KRAS-mutant colorectal cancer mouse model under MEK162 treatment [47]. On the other hand, several studies also showed that treatment with a MEKi (selumetinib) induced amplification of B-RAF, which in turn reduced the efficacy of the MEKi to inhibit ERK [15], [34].…”

Section: Discussionsupporting

confidence: 93%

Cyclical Treatment of Colorectal Tumor Spheroids Induces Resistance to MEK Inhibitors

Thakuri

Luker

Tavana

2019

Translational Oncology

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Adaptive drug resistance is a major obstacle to successful treatment of colorectal cancers. Physiologic tumor models of drug resistance are crucial to understand mechanisms of treatment failure and improve therapy by developing new therapeutics and treatment strategies. Using our aqueous two-phase system microtechnology, we developed colorectal tumor spheroids and periodically treated them with sub-lethal concentrations of three Mitogen Activated Kinase inhibitors (MEKi) used in clinical trials. We used long-term, periodic treatment and recovery of spheroids to mimic cycles of clinical chemotherapy and implemented a growth rate metric to quantitatively assess efficacy of the MEKi during treatment. Our results showed that efficacy of the MEKi significantly reduced with increased treatment cycles. Using a comprehensive molecular analysis, we established that resistance of colorectal tumor spheroids to the MEKi developed through activation of the PI3K/AKT/mTOR pathway. We also showed that other potential feedback mechanisms, such as STAT3 activation or amplified B-RAF, did not account for resistance to the MEKi. We combined each of the three MEKi with a PI3K/mTOR inhibitor and showed that the combination treatments synergistically blocked resistance to the MEKi. Importantly, and unlike the individual inhibitors, we demonstrated that synergistic concentrations of combinations of MEK and PI3K/mTOR inhibitors effectively inhibited growth of colorectal tumor spheroids in long-term treatments. This proof-of-concept study to model treatment-induced drug resistance of cancer cells using 3D cultures offers a unique approach to identify underlying molecular mechanisms and develop effective treatments.

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Section: Discussionsupporting

confidence: 93%

Cyclical Treatment of Colorectal Tumor Spheroids Induces Resistance to MEK Inhibitors

Thakuri

Luker

Tavana

2019

Translational Oncology

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“…Several studies have shown that inhibition of both the MAPK and PI3K pathways is more effective in Ras mutant cancers than either inhibitor alone [28, 29], leading to the development of dual inhibitors of the two pathways [30, 31]. We thus synthesized D-87503, a dual inhibitor of both ERK and PI3K [31]; the structure is shown in Figure 5A.…”

Section: Resultsmentioning

confidence: 99%

Blocking downstream signaling pathways in the context of HDAC inhibition promotes apoptosis preferentially in cells harboring mutant Ras

et al. 2016

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We previously demonstrated activation of the mitogen-activated protein kinase (MAPK) pathway in a series of romidepsin-selected T-cell lymphoma cell lines as a mechanism of resistance to the histone deacetylase inhibitor (HDI), romidepsin. As Ras mutation leads to activation of both the MAPK and the phosphoinositide 3-kinase (PI3K) pathway, we examined whether combining romidepsin with small molecule pathway inhibitors would lead to increased apoptosis in cancers harboring Ras mutations. We treated 18 Ras mutant or wild-type cell lines with romidepsin in the presence of a MEK inhibitor (PD-0325901) and/or an AKT inhibitor (MK-2206) and examined apoptosis by flow cytometry. A short-term treatment schedule of romidepsin (25 ng/ml for 6 h) was used to more closely model clinical administration. Romidepsin in combination with a MEK and an AKT inhibitor induced apoptosis preferentially in cells harboring mutant versus wild-type Ras (69.1% vs. 21.1%, p < 0.0001). Similar results were found in a subset of cell lines when belinostat was combined with the MEK and AKT inhibitors and when romidepsin was combined with the dual extracellular signaling-related kinase (ERK)/PI3K inhibitor, D-87503, which inhibited both the MAPK and PI3K pathways at 5–10 μM. The observed apoptosis was caspase-dependent and required Bak and Bax expression. Cells with wild-type or mutant Ras treated with romidepsin alone or in combination with the MEK inhibitor displayed increased expression of proapoptotic Bim. We thus conclude that cancers bearing Ras mutations, such as pancreatic cancer, can be targeted by the combination of an HDI and a dual inhibitor of the MAPK and PI3K pathways.

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“…There is a cross talk between PI3K/Akt and MEK/ERK signaling pathways. Some study reported that they can regulate each other's activity [ 14 – 21 ]. It has been shown that chemical MEK inhibitor may have a feedback effect to activate PI3K/Akt signaling in certain type cells [ 17 , 22 ].…”

Section: Resultsmentioning

confidence: 99%

Blockade efficacy of MEK/ERK-dependent autophagy enhances PI3K/Akt inhibitor NVP-BKM120's therapeutic effectiveness in lung cancer cells

et al. 2016

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NVP-BKM120 (BKM120) is a new pan-class I phosphatidylinositol-3 kinase (PI3K) inhibitor and has been tested in clinical trials as an anticancer agent. In this study, we determined whether BKM120 induces autophagy and the impact of autophagy induction on BKM120's growth-inhibitory activity. BKM120 potently induced elevation of autophagosome-bound type II LC3 (LC3-II) protein, predominantly in cell lines insensitive to BKM120, thereby inducing autophagy. The presence of lysosomal protease inhibitor chloroquine further enhanced the levels of LC3-II. BKM120 combined with chloroquine, enhanced growth-inhibitory effects including induction of apoptosis, suggesting that autophagy is a protective mechanism counteracting BKM120's growth-inhibitory activity. Interestingly, BKM120 increased p-ERK1/2 levels. When blocking the activation of this signaling with MEK inhibitors or with knockdown of ERK1/2, the ability of BKM120 to increase LC3-II was attenuated and the growth-inhibitory effects including induction of apoptosis were accordingly enhanced, suggesting that the MEK/ERK activation contributes to BKM120-induced authophagy. In mouse xenograft model, we also found that the combination of BKM120 and PD0325901 synergistically suppressed cell growth in human lung cancer cells. Thus, the current study not only reveals mechanisms accounting for BKM120-induced autophagy, but also suggests an alternative method to enhance BKM120's therapeutic efficacy against non-small cell lung cancer(NSCLC) by blocking autophagy with either a lysosomal protease inhibitor or MEK inhibitor.

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Assessment of the In Vivo Activity of PI3K and MEK Inhibitors in Genetically Defined Models of Colorectal Cancer

Cited by 14 publications

References 35 publications

Cyclical Treatment of Colorectal Tumor Spheroids Induces Resistance to MEK Inhibitors

Cyclical Treatment of Colorectal Tumor Spheroids Induces Resistance to MEK Inhibitors

Blocking downstream signaling pathways in the context of HDAC inhibition promotes apoptosis preferentially in cells harboring mutant Ras

Blockade efficacy of MEK/ERK-dependent autophagy enhances PI3K/Akt inhibitor NVP-BKM120's therapeutic effectiveness in lung cancer cells

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