Dual Targeting of Akt and mTORC1 Impairs Repair of DNA Double-Strand Breaks and Increases Radiation Sensitivity of Human Tumor Cells

Holler, Marina; Grottke, Astrid; Mueck, Katharina; Manes, Julia; Jücker, Manfred; Rodemann, H. Peter; Toulany, Mahmoud

doi:10.1371/journal.pone.0154745

Cited by 41 publications

(50 citation statements)

References 51 publications

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“…Prior to assessing lower doses for inhibitors targeting PI3K/AKT, it is critical to identify other pathways that will sensitize cells to inhibition of PI3K/AKT. For example, targeting mTOR in addition to AKT has been shown to enhance efficacy [ 37 , 38 ], suggesting mTOR is a potential co-target with PI3K/AKT. Interestingly, mTOR has also been shown to activate HSF1 [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Combined inhibition of AKT and HSF1 suppresses breast cancer stem cells and tumor growth

et al. 2017

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Breast cancer is the most common cancer in women and the second leading cause of cancer deaths in women. Over 90% of breast cancer deaths are attributable to metastasis. Our lab has recently reported that AKT activates heat shock factor 1 (HSF1), leading to epithelial-to-mesenchymal transition in HER2-positive breast cancer. However, it is unknown whether the AKT-HSF1 pathway plays an important role in other breast cancer subtypes, breast cancer stem cells, or breast cancer growth and metastasis. Herein, we showed AKT and HSF1 to be frequently co-activated in breast cancer cell lines and specimens across different subtypes. Activated AKT (S473) and HSF1 (S326) are strongly associated with shortened time to metastasis. Inhibition of the AKT-HSF1 signaling axis using small molecule inhibitors, HSF1 knockdown or the dominant-negative HSF1 mutant (S326A) reduced the growth of metastatic breast cancer cells and breast cancer stem cells. The combination of small molecule inhibitors targeting AKT (MK-2206) and HSF1 (KRIBB11) resulted in synergistic killing of breast cancer cells and breast cancer stem cells across different molecular subtypes. Using an orthotopic xenograft mouse model, we found that combined targeting of AKT and HSF1 to significantly reduce tumor growth, induce tumor apoptosis, delay time to metastasis, and prolong host survival. Taken together, our results indicate AKT-HSF1 signaling mediates breast cancer stem cells self-renewal, tumor growth and metastasis, and that dual targeting of AKT and HSF1 resulted in synergistic suppression of breast cancer progression thereby supporting future testing of AKT-HSF1 combination therapy for breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

Combined inhibition of AKT and HSF1 suppresses breast cancer stem cells and tumor growth

et al. 2017

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“…The PI3K pathway can be targeted at the level of PI3K, AKT and mTOR and even dual inhibitors of the pathway exist, targeting both PI3K and mTOR. The general response that has been observed for the combination of PI3K pathway inhibition with photon irradiation is an enhanced sensitivity of the cancer cells to radiation (197)(198)(199)(200)(201). No studies have investigated the combination of PI3K pathway inhibitors with proton irradiation.…”

Section: Inhibition Of Egfr Pathwaymentioning

confidence: 99%

Combination Therapy With Charged Particles and Molecular Targeting: A Promising Avenue to Overcome Radioresistance

et al. 2020

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Radiotherapy plays a central role in the treatment of cancer patients. Over the past decades, remarkable technological progress has been made in the field of conventional radiotherapy. In addition, the use of charged particles (e.g., protons and carbon ions) makes it possible to further improve dose deposition to the tumor, while sparing the surrounding healthy tissues. Despite these improvements, radioresistance and tumor recurrence are still observed. Although the mechanisms underlying resistance to conventional radiotherapy are well-studied, scientific evidence on the impact of charged particle therapy on cancer cell radioresistance is restricted. The purpose of this review is to discuss the potential role that charged particles could play to overcome radioresistance. This review will focus on hypoxia, cancer stem cells, and specific signaling pathways of EGFR, NFκB, and Hedgehog as well as DNA damage signaling involving PARP, as mechanisms of radioresistance for which pharmacological targets have been identified. Finally, new lines of future research will be proposed, with a focus on novel molecular inhibitors that could be used in combination with charged particle therapy as a novel treatment option for radioresistant tumors.

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“…Similarly, potentiating the cytotoxic effects of radiotherapy through radiosensitization, the therapeutic effects of radiotherapy may be improved [13]. Compounds that target the DNA-damage response mechanisms initiated as a result of ionizing radiation are of particular interest for use in combination with radiotherapy [14,15]. At the very center of the radiation response pathways is the well-known transcription factor p53 [16].…”

Section: Introductionmentioning

confidence: 99%

Enhancing the therapeutic effects of in vitro targeted radionuclide therapy of 3D multicellular tumor spheroids using the novel stapled MDM2/X-p53 antagonist PM2

et al. 2020

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Background: Precision therapeutics continuously make advances in cancer therapy, and a field of growing interest is the combination of targeted radionuclide therapy (TRNT) with potential radiosensitizing agents. This study evaluated whether the effects of in vitro TRNT, using the 177 Lu-labeled anti-CD44v6 antibody AbN44v6, were potentiated by the novel stapled MDM2/X-p53 antagonist PM2. Materials and methods: Two wt p53 cell lines, HCT116 (colorectal carcinoma) and UM-SCC-74B (head and neck squamous cell carcinoma), expressing different levels of the target antigen, CD44v6, were used. Antigen-specific binding of 177 Lu-AbN44v6 was initially verified in a 2D cell assay, after which the potential effects of unlabeled AbN44v6 on downstream phosphorylation of Erk1/2 were evaluated by western blotting. Further, the therapeutic effects of unlabeled AbN44v6, 177 Lu-AbN44v6, PM2, or a combination (labeled/unlabeled AbN44v6 +/− PM2) were assessed in 3D multicellular tumor spheroid assays. Results: Radiolabeled antibody bound specifically to CD44v6 on both cell lines. Unlabeled AbN44v6 binding did not induce downstream phosphorylation of Erk1/2 at any of the concentrations tested, and repeated treatments with the unlabeled antibody did not result in any spheroid growth inhibition. 177 Lu-AbN44v6 impaired spheroid growth in a dose-dependent and antigen-dependent manner. A single modality treatment with 20 μM of PM2 significantly impaired spheroid growth in both spheroid models. Furthermore, the combination of TRNT and PM2based therapy proved significantly more potent than either monotherapy. In HCT116 spheroids, this resulted in a two-and threefold spheroid growth rate decrease for the combination of PM2 and 100 kBq 177 Lu-AbN44v6 compared to monotherapies 14-day post treatment. In UM-SCC-74B spheroids, the combination therapy resulted in a reduction in spheroid size compared to the initial spheroid size 10-day post treatment. Conclusion: TRNT using 177 Lu-AbN44v6 proved efficient in stalling spheroid growth in a dose-dependent and antigen-dependent manner, and PM2 treatment demonstrated a growth inhibitory effect as a monotherapy. Moreover, by combining TRNT with PM2-based therapy, therapeutic effects of TRNT were potentiated in a 3D multicellular tumor spheroid model. This proof-of-concept study exemplifies the strength and possibility of combining TRNT targeting CD44v6 with PM2-based therapy.

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Dual Targeting of Akt and mTORC1 Impairs Repair of DNA Double-Strand Breaks and Increases Radiation Sensitivity of Human Tumor Cells

Cited by 41 publications

References 51 publications

Combined inhibition of AKT and HSF1 suppresses breast cancer stem cells and tumor growth

Combined inhibition of AKT and HSF1 suppresses breast cancer stem cells and tumor growth

Combination Therapy With Charged Particles and Molecular Targeting: A Promising Avenue to Overcome Radioresistance

Enhancing the therapeutic effects of in vitro targeted radionuclide therapy of 3D multicellular tumor spheroids using the novel stapled MDM2/X-p53 antagonist PM2

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