Combined PI3K/mTOR and MEK Inhibition Provides Broad Antitumor Activity in Faithful Murine Cancer Models

Roberts, Patrick; Usary, Jerry; Darr, David B.; Dillon, Patrick M.; Pfefferle, Adam D.; Whittle, Martin C.; Duncan, James S.; Johnson, Søren M.; Combest, Austin J.; Jin, Jian; Zamboni, William C.; Johnson, Gary L.; Perou, Charles M.; Sharpless, Norman E.

doi:10.1158/1078-0432.ccr-12-0563

Cited by 122 publications

(124 citation statements)

References 46 publications

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“…In fact, in tumor treatment, it was said that there were limitations of monotherapy for inhibiting feedbackregulated pathways and suggested that combined treatment with mTOR and P3IK/MAPK inhibitors would show more anti-tumor activity in a wide range of human malignance. 42 In line with this idea, we hypothesized that if rapamycin was used for the treatment of fibrotic diseases, combined inhibition of PI3K and mTOR pathways may have additive anti-fibrotic effects. Further in vivo studies should be designed to determine whether these findings are value.…”

Section: Resultsmentioning

confidence: 99%

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Dai

Geng

et al. 2015

Laboratory Investigation

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Excessive production of connective tissue growth factor (CTGF, CCN2) and increased motor ability of the activated fibroblast phenotype contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, molecules and signal pathways regulating CCN2 expression and migration of lung fibroblasts are still elusive. We hypothesize that rapamycin, via binding and blocking mammalian target of rapamycin (mTOR) complex (mTORC), affects CCN2 expression and migration of lung fibroblasts in vitro. Primary normal and fibrotic human lung fibroblasts were isolated from lung tissues of three patients with primary spontaneous pneumothorax and three with IPF. Cells were incubated with regular medium, or medium containing rapamycin, human recombinant transforming growth factor (TGF)-β1, or both. CCN2 and tissue inhibitor of metalloproteinase (TIMP)-1 expression in cells or supernatant was detected. Wound healing and migration assay was used to measure the migratory potential. TGF-β type I receptor (TβRI)/Smad inhibitor, SB431542 and phosphoinositide 3-kinase (PI3K) inhibitor, LY294002 were used to determine rapamycin's mechanism of action. We demonstrated that rapamycin amplified basal or TGF-β1-induced CCN2 mRNA and protein expression in normal or fibrotic fibroblasts by Smad-independent but PI3K-dependent pathway. Additionally, rapamycin also enhanced TIMP-1 expression as indicated by ELISA. However, wound healing and migrating assay showed rapamycin did not affect the mobility of fibroblasts. Collectively, this study implies a significant fibrogenic induction activity of rapamycin by activating AKT and inducing CCN2 expression in vitro and provides the possible mechanisms for the in vivo findings which previously showed no antifibrotic effect of rapamycin on lung fibrosis.

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Section: Resultsmentioning

confidence: 99%

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Dai

Geng

et al. 2015

Laboratory Investigation

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“…The MEK/ERK and the PI3K/mTOR cascade are prototypic survival pathways that have been implicated in tumorogenesis of NRAS mutant melanoma (9,21). Emerging preclinical evidence suggests that combined targeting of these two pathways with selective small-molecule inhibitors might be effective in treating malignancies with preexistent or acquired RAS mutations (22)(23)(24)(25). In this study, we demonstrate that MEKi combined with PI3K/mTOR 1,2 inhibition is able to synergistically reduce cell viability in vitro and decrease tumor size in vivo in a large panel of human NRAS mutant melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo

Posch

Moslehi

Feeney

et al. 2013

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

206

214

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Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog (NRAS) gene are common genetic events in malignant melanoma being found in 15-25% of cases. NRAS is thought to activate both mitogen activated protein kinase (MAPK) and PI3K signaling in melanoma cells. We studied the influence of different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant melanoma cells. In general, these cells were more sensitive to MEK inhibition compared with inhibition in the PI3K/ mTOR cascade. Combined targeting of MEK and PI3K was superior to MEK and mTOR 1,2 inhibition in all NRAS mutant melanoma cell lines tested, suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR 1,2 in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. Furthermore, we showed that MEK and PI3K/mTOR 1,2 inhibition is synergistic. Expression analysis confirms that combined MEK and PI3K/mTOR 1,2 inhibition predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor receptor pathways, which signal through MEK/ERK and PI3K/mTOR, respectively. Our results suggest that combined targeting of the MEK/ERK and PI3K/mTOR pathways has antitumor activity and might serve as a therapeutic option in the treatment of NRAS mutant melanoma, for which there are currently no effective therapies.O ncogenic mutations in codons 12, 13, or 61 of the rat sarcoma (RAS) family of small GTPases, Kirsten rat sarcoma viral oncogene homolog (KRAS), Harvey rat sarcoma viral oncogene homolog (HRAS), and neuroblastoma RAS viral oncogene homolog (NRAS) occur in approximately one-third of all human cancers with NRAS mutations found in about 15-20% of melanomas (1-7). Mutated RAS proteins activate signaling pathways that promote the cell division cycle and cell growth and suppress apoptosis. Small interfering RNA (siRNA)-mediated depletion of NRAS in melanoma cell lines inhibits proliferation and renders cells sensitive to chemotherapy, making mutant NRAS and its signaling effectors relevant targets for melanoma therapy (8, 9). Efforts at developing therapeutics that inhibit mutant RAS directly have so far not been successful. The high affinity of RAS for GTP and the high concentrations of GTP intracellularly has meant that the identification of small molecules, which selectively prevent accumulation of RAS-GTP, has not been possible (10). Targeting mutant NRAS with siRNA is still limited to preclinical models because of the significant challenge in delivering antisense oligonucleotides in vivo. The response of NRAS mutant melanoma and other melanomas to various chemotherapeutic regiments has been very scarce with only 6% of patients responding (11). Alternatively, farnesyltransferase inhibitors (FTIs) were thought to inhibit RAS activation by blocking farnesy...

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“…Studies using the MMTV-c-neu mouse model (a mouse model for breast cancer generated by the overexpression of the rat ortholog of HER2 V659E ) have shown evidence of the antitumor activity of lapatinib ( 10,11 ).…”

Section: Research Brief Functional Analysis Of Her2 V659ementioning

confidence: 99%

Clinical Response to a Lapatinib-Based Therapy for a Li-Fraumeni Syndrome Patient with a Novel HER2V659E Mutation

et al. 2013

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Genomic characterization of recurrent breast and lung tumors developed over the course of 10 years in a 29-year-old patient with a germline TP53 mutation (LiFraumeni Syndrome) identifi ed oncogenic alterations in the HER2 and EGFR genes across all tumors, including HER2 amplifi cations, an EGFR -exon 20 insertion, and the fi rst-in-humans HER2 V659E mutation showing a phenotypic convergent evolution toward HER2 and EGFR alterations. Following the identifi cation of HER2-activating events in the most recent lung carcinoma and in circulating tumor cells, we treated the reminiscent metastatic lesions with a lapatinib-based therapy. A symptomatic and radiologic clinical response was achieved. HER2 V659E sensitivity to lapatinib was confi rmed in the laboratory. SIGNIFICANCE:The precise knowledge of the genomic alterations present in tumors is critical to selecting the optimal treatment for each patient. Here, we report the molecular characterization and clinical response to a lapatinib-based therapy for the tumors of a Li-Fraumeni patient showing prevalence of HER2 and EGFR genomic alterations. Cancer Discov; 3(11); 1238-44.

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Combined PI3K/mTOR and MEK Inhibition Provides Broad Antitumor Activity in Faithful Murine Cancer Models

Cited by 122 publications

References 46 publications

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo

Clinical Response to a Lapatinib-Based Therapy for a Li-Fraumeni Syndrome Patient with a Novel HER2V659E Mutation

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