IGF-1R inhibition sensitizes breast cancer cells to ATM-related kinase (ATR) inhibitor and cisplatin

O’Flanagan, Ciara H.; O'Shea, Sandra; Lyons, Alan M.; Fogarty, Fionola; McCabe, Nuala; Kennedy, Richard D.; O’Connor, Rosemary

doi:10.18632/oncotarget.10862

Cited by 29 publications

(22 citation statements)

References 55 publications

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“…Acute inhibition of IGF-1R or PI3K reduced expression of both PGC-1␤ and PRC and caused decreased mitochondrial mass and biogenesis. Mitochondrial biogenesis was also reduced in an MCF-7 cell line variant (MCF-7-R) that was derived for adaptive resistance to the IGF-1R kinase inhibitor BMS-754807 (23). These cells exhibited increased mitochondrial mass, high ROS levels, and decreased expression of markers of mitochondrial biogenesis, although NFE2L2/NRF-2 levels were increased, which may contribute to survival and antioxidant protection.…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondrial reprogramming and a reliance on oxidative phosphorylation have been associated with resistance to MAPK and PI3K inhibitors and with tumor recurrence following oncogene ablation (10,22). It was thus interesting to investigate the impact of chronic IGF-1R inhibition on mitochondrial function and cell phenotype in an MCF-7 cell line variant (MCF-7R) we had selected for acquired resistance to the kinase inhibitor BMS-754807 (23). As can be seen in Fig.…”

Section: Mitochondrial Dysfunction and Reduced Biogenesis Upon Supprementioning

confidence: 99%

“…BMS-754807-resistant MCF-7 cells (MCF-7-R cells) were derived from MCF-7 cells that were cultured in increasing stepwise increments of BMS-754807, starting at 100 nM BMS-754807, until cells were proliferating successfully in the presence of each increased drug concentration and a resistant pool had been generated; they have been described previously (23). Cells were then permanently maintained in DMEM containing 500 nM BMS-754807.…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

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Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells

Lyons¹,

Coleman²,

Riis³

et al. 2017

Journal of Biological Chemistry

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Mitochondrial activity and metabolic reprogramming influence the phenotype of cancer cells and resistance to targeted therapy. We previously established that an insulin-like growth factor 1 (IGF-1)-inducible mitochondrial UTP carrier (PNC1/SLC25A33) promotes cell growth. This prompted us to investigate whether IGF signaling is essential for mitochondrial maintenance in cancer cells and whether this contributes to therapy resistance. Here we show that IGF-1 stimulates mitochondrial biogenesis in a range of cell lines. In MCF-7 and ZR75.1 breast cancer cells, IGF-1 induces peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) and PGC-1α-related coactivator (PRC). Suppression of PGC-1β and PRC with siRNA reverses the effects of IGF-1 and disrupts mitochondrial morphology and membrane potential. IGF-1 also induced expression of the redox regulator nuclear factor-erythroid-derived 2-like 2 (NFE2L2 alias NRF-2). Of note, MCF-7 cells with acquired resistance to an IGF-1 receptor (IGF-1R) tyrosine kinase inhibitor exhibited reduced expression of PGC-1β, PRC, and mitochondrial biogenesis. Interestingly, these cells exhibited mitochondrial dysfunction, indicated by reactive oxygen species expression, reduced expression of the mitophagy mediators BNIP3 and BNIP3L, and impaired mitophagy. In agreement with this, IGF-1 robustly induced BNIP3 accumulation in mitochondria. Other active receptor tyrosine kinases could not compensate for reduced IGF-1R activity in mitochondrial protection, and MCF-7 cells with suppressed IGF-1R activity became highly dependent on glycolysis for survival. We conclude that IGF-1 signaling is essential for sustaining cancer cell viability by stimulating both mitochondrial biogenesis and turnover through BNIP3 induction. This core mitochondrial protective signal is likely to strongly influence responses to therapy and the phenotypic evolution of cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Mitochondrial Dysfunction and Reduced Biogenesis Upon Supprementioning

confidence: 99%

Section: Cell Lines and Cell Culturementioning

confidence: 99%

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Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells

Lyons¹,

Coleman²,

Riis³

et al. 2017

Journal of Biological Chemistry

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“…Consistently, PH665752 enhanced the radio-sensitivity of cancer cells through severe DNA damage [15]. Another report suggested the critical role of IGF1-IGF receptor for producing radio-resistance via sequential activation of IGF→IGFR→PI3K→AKT→ATR pathways [16]. Thus, growth factors, such as HGF, secreted from cancer cells may be a trigger for activating ATR signaling cascades to reduce (or reverse) DNA damage in an early process of chemotherapy or X-ray irradiation.…”

Section: Atr Cascade Inhibition Strategymentioning

confidence: 91%

DNA-Checkpoint Kinase, ATR is a Promising Target for Synthetic Lethality-Aimed Anti-Tumor Therapy

Mizuno¹,

Osaki²

2018

J Tumor Res

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Cancer cells constitutively undergo DNA damages, in response to oxidant stresses, or during chemo-or radio-therapy. DNA checkpoint kinases, such as ATR, are important for cancer cells to overcome DNA damages, resulting in acquiring resistance. In this process, ATR kinase plays a key role in protecting cancer cells through DNA replication. In other words, ATR inhibition can be a reasonable strategy to release chemo-and radio-resistance. Now, clinical trials using ATR chemical inhibitors (i.e., phase-I/II) are ongoing worldwide, with a focus on its synergic effect on DNA-damaging drugs or irradiation.

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“…Finally, several IGF-1R inhibitors have been tested in clinical trials but, to date, have failed to show any clinical benefit in unselected patients [ 84 ].…”

Section: Targeted Therapies For the Treatment Of Advanced Breast Cmentioning

confidence: 99%

Molecular Biomarkers for Prediction of Targeted Therapy Response in Metastatic Breast Cancer: Trick or Treat?

Toss

Venturelli

Peterle

et al. 2017

IJMS

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Abstract:In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving the prognosis of this disease. These drugs target specific molecular abnormalities that confer a survival advantage to cancer cells. On these bases, emerging evidence from clinical trials provided increasing proof that the genetic landscape of any tumor may dictate its sensitivity or resistance profile to specific agents and some studies have already showed that tumors treated with therapies matched with their molecular alterations obtain higher objective response rates and longer survival. Predictive molecular biomarkers may optimize the selection of effective therapies, thus reducing treatment costs and side effects. This review offers an overview of the main molecular pathways involved in breast carcinogenesis, the targeted therapies developed to inhibit these pathways, the principal mechanisms of resistance and, finally, the molecular biomarkers that, to date, are demonstrated in clinical trials to predict response/resistance to targeted treatments in metastatic breast cancer.

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IGF-1R inhibition sensitizes breast cancer cells to ATM-related kinase (ATR) inhibitor and cisplatin

Cited by 29 publications

References 55 publications

Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells

Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells

DNA-Checkpoint Kinase, ATR is a Promising Target for Synthetic Lethality-Aimed Anti-Tumor Therapy

Molecular Biomarkers for Prediction of Targeted Therapy Response in Metastatic Breast Cancer: Trick or Treat?

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