Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors

Echeverry, Nohemy; Ziltener, Gabriela; Barbone, Dario; Weder, Walter; Stahel, Rolf A.; Broaddus, V. Courtney; Felley‐Bosco, Emanuela

doi:10.1038/cddis.2015.124

Cited by 45 publications

(45 citation statements)

References 68 publications

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“…Consistent with this observation, Manara et al showed that NVP-BEZ235 induced sarcoma stasis, by arresting cells in G1 phase of the cell cycle, without remarkable effects on apoptosis (13). It was postulated that autophagy induced by NVP-BEZ235 was a pro-survival mechanism which rendered tumor cells capable of anti-apoptosis surviving in the kinase inhibitor (25)(26)(27).…”

Section: Discussionsupporting

confidence: 50%

Oridonin enhances the anticancer activity of NVP-BEZ235 against neuroblastoma cells in vitro and in vivo through autophagy

Zhang

Liu

et al. 2016

International Journal of Oncology

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Abstract. The aberrant activation of PI3K/Akt/mTOR signaling pathway plays an important role in the oncogenesis, prognosis and chemotherapy resistance of neuroblastoma. However, NVP-BEZ235, a potent dual PI3K and mTOR inhibitor have not shown beneficial effects on neuroblastoma especially in terms of apoptosis induction as a single agent. We therefore attempted to explore an effective combination regimen to enhance the anticancer activity of NVP-BEZ235. Interestingly, we found that oridonin, a natural biologically active compound extracted from the Chinese medicinal herb Rabdosia rubescens, combined with NVP-BEZ235 markedly induced apoptosis of neuroblastoma cells. Notably, the synergistic activation of the apoptotic pathway was accompanied with enhanced autophagy as evidenced by significant decreased p62 expression as well as upregulated conversion of LC3-II. Suppression of the Beclin-1, a core component of the autophagy machinery, by means of shRNA resulted in diminished synergistic antitumor effect. Furthermore, the co-treatment with oridonin and NVP-BEZ235 was also much more effective than either agent alone in inhibiting the growth of neuroblastoma xenografts and in inducing tumor cells apoptosis. Taken together, our results suggest that the combination of NVP-BEZ235 and oridonin is a novel and potential strategy for neuroblastoma therapy.

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Section: Discussionsupporting

confidence: 50%

Oridonin enhances the anticancer activity of NVP-BEZ235 against neuroblastoma cells in vitro and in vivo through autophagy

Zhang

Liu

et al. 2016

International Journal of Oncology

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“…Thus, we hypothesize that in BLCAb001, but not in BLCAb002, inhibition of PI3K may induce a feed-back upregulation of receptor tyrosine kinases and, consequently, re-induction of pAKT and sustained autophagy, as reported in other tumor systems [59]. Recent studies have shown activation of autophagy as one of the critical molecular alterations that limits the anti-tumor effects of PI3K/mTOR inhibitors [60]. Our RNAseq data showed BNIP3 and BCL11A upregulation, and ULK2, BAG1, RAB11FIP4 and BCLL14 downregulation in BLCAb001 tumors, mirroring the higher levels of LC3B I/II by Western blot analysis (Figure 5A and 5B).…”

Section: Discussionmentioning

confidence: 99%

Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts

et al. 2016

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PurposeEffective systemic therapeutic options are limited for bladder cancer. In this preclinical study we tested whether bladder cancer gene alterations may be predictive of treatment response.Experimental designWe performed genomic profiling of two bladder cancer patient derived tumor xenografts (PDX). We optimized the exome sequence analysis method to overcome the mouse genome interference.ResultsWe identified a number of somatic mutations, mostly shared by the primary tumors and PDX. In particular, BLCAb001, which is less responsive to cisplatin than BLCAb002, carried non-sense mutations in several genes associated with cisplatin resistance, including MLH1, BRCA2, and CASP8. Furthermore, RNA-Seq analysis revealed the overexpression of cisplatin resistance associated genes such as SLC7A11, TLE4, and IL1A in BLCAb001. Two different PIK3CA mutations, E542K and E545K, were identified in BLCAb001 and BLCAb002, respectively. Thus, we tested whether the genomic profiling was predictive of response to a dual PI3K/mTOR targeting agent, LY3023414. Despite harboring similar PIK3CA mutations, BLCAb001 and BLCAb002 exhibited differential response, both in vitro and in vivo. Sustained target modulation was observed in the sensitive model BLCAb002 but not in BLCAb001, as well as decreased autophagy. Interestingly, computational modelling of mutant structures and affinity binding to PI3K revealed that E542K mutation was associated with weaker drug binding than E545K.ConclusionsOur results suggest that the presence of activating PIK3CA mutations may not necessarily predict in vivo treatment response to PI3K targeted therapies, while specific gene alterations may be predictive for cisplatin response in bladder cancer models and, potentially, in patients as well.

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“…Autophagy has been suggested to promote resistance to inhibitors of the PI3K pathway (24,43). CQ is being investigated as an autophagy inhibitor in both preclinical and clinical studies.…”

Section: Cq Treatment Blocks Autophagy Induced By Pi3k Inhibition Andmentioning

confidence: 99%

“…Thus, autophagy is an attractive therapeutic target for cancer. PI3K and mTOR inhibition can induce autophagy, and inhibition of autophagy enhances the growth-suppressive and apoptotic effects of PI3K/mTOR inhibition (22)(23)(24).…”

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confidence: 99%

Autophagy promotes escape from phosphatidylinositol 3‐kinase inhibition in estrogen receptor‐positive breast cancer

et al. 2018

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Hyperactivation of the PI3K pathway has been implicated in resistance to antiestrogen therapies in estrogen receptor α (ER)-positive breast cancer, prompting the development of therapeutic strategies to inhibit this pathway. Autophagy has tumor-promoting and -suppressing roles and has been broadly implicated in resistance to anticancer therapies, including antiestrogens. Chloroquine (CQ) is an antimalarial and amebicidal drug that inhibits autophagy in mammalian cells and human tumors. Herein, we observed that CQ inhibited proliferation and autophagy in ER breast cancer cells. PI3K inhibition with GDC-0941 (pictilisib) induced autophagy. Inhibition of autophagy using CQ or RNA interference potentiated PI3K inhibitor-induced apoptosis. Combined inhibition of PI3K and autophagy effectively induced mitochondrial membrane depolarization, which required the BH3-only proapoptotic proteins Bim and PUMA. Treatment with GDC-0941, CQ, or the combination, significantly suppressed the growth of ER breast cancer xenografts in mice. In an antiestrogen-resistant xenograft model, GDC-0941 synergized with CQ to provide partial, but durable, tumor regression. These findings warrant clinical evaluation of therapeutic strategies to target ER, PI3K, and autophagy for the treatment of ER breast cancer.-Yang, W., Hosford, S. R., Traphagen, N. A., Shee, K., Demidenko, E., Liu, S., Miller, T. W. Autophagy promotes escape from phosphatidylinositol 3-kinase inhibition in estrogen receptor-positive breast cancer.

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Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors

Cited by 45 publications

References 68 publications

Oridonin enhances the anticancer activity of NVP-BEZ235 against neuroblastoma cells in vitro and in vivo through autophagy

Oridonin enhances the anticancer activity of NVP-BEZ235 against neuroblastoma cells in vitro and in vivo through autophagy

Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts

Autophagy promotes escape from phosphatidylinositol 3‐kinase inhibition in estrogen receptor‐positive breast cancer

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