Dual inhibition of IGF1R and ER enhances response to trastuzumab in HER2 positive breast cancer cells

McDermott, Martina S.J.; Ivers, Laura; Browne, Brigid C.; Madden, Stephen F.; O’Brien, Neil A.; Crown, John; O’Donovan, Norma

doi:10.3892/ijo.2017.3976

Cited by 26 publications

(20 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this line, we found that NRP1 is also upregulated in HER2-addicted breast cancer cells subjected to targeted therapy. NRP1 is pivotal in this system to induce IGF1R tyrosine kinase expression and activity, a mechanism known to mediate resistance to HER2-targeted inhibitors (45). Similar to what we observed for melanoma, NRP1 upregulation is frequently seen in breast cancer samples upon treatment with HER2 inhibitors.…”

Section: Discussionsupporting

confidence: 81%

Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies

Rizzolio¹,

Cagnoni²,

Battistini³

et al. 2018

Journal of Clinical Investigation

View full text Add to dashboard Cite

Cancer cell dependence on activated oncogenes is therapeutically targeted, but acquired resistance is virtually unavoidable. Here we show that the treatment of addicted melanoma cells with BRAF inhibitors, and of breast cancer cells with HER2-targeted drugs, led to an adaptive rise in neuropilin-1 (NRP1) expression, which is crucial for the onset of acquired resistance to therapy. Moreover, NRP1 levels dictated the efficacy of MET oncogene inhibitors in addicted stomach and lung carcinoma cells. Mechanistically, NRP1 induced a JNK-dependent signaling cascade leading to the upregulation of alternative effector kinases EGFR or IGF1R, which in turn sustained cancer cell growth and mediated acquired resistance to BRAF, HER2, or MET inhibitors. Notably, the combination with NRP1-interfering molecules improved the efficacy of oncogene-targeted drugs and prevented or even reversed the onset of resistance in cancer cells and tumor models. Our study provides the rationale for targeting the NRP1-dependent upregulation of tyrosine kinases, which are responsible for loss of responsiveness to oncogene-targeted therapies.

show abstract

Section: Discussionsupporting

confidence: 81%

Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies

Rizzolio¹,

Cagnoni²,

Battistini³

et al. 2018

Journal of Clinical Investigation

View full text Add to dashboard Cite

show abstract

“…In order to exploit the anti‐tumourigenic responses to INSR/IGF1R inhibition seen in preclinical experiments, current investigations are concentrating on combinatorial studies using IGF inhibitors. Combination with other RTK TKIs is used as a means of reducing the emergence of resistance or in addition to either standard chemotherapeutic agents or radiotherapy utilizing their properties as chemo‐ and radiosensitizers, respectively (McDermott et al ., ; Schaffrath et al ., ). Given the importance of the PI3K/AKT pathway in TGCT, simultaneous multiple targeting of this pathway may be effective in TGCT patients by combining IGF1R inhibition with other inhibitors of this pathway.…”

Section: Therapeutic Targeting Of the Igf System In Cancermentioning

confidence: 99%

IGF signalling in germ cells and testicular germ cell tumours: roles and therapeutic approaches

Selfe

Shipley

2019

Andrology

View full text Add to dashboard Cite

The insulin‐like growth factor (IGF) axis plays key roles in normal tissue growth and development as well as in the progression of several tumour types and their subsequent growth and progression to a metastatic phenotype. This review explores the role of IGF system in normal germ cell development and function in addition to examining the evidence for deregulation of IGF signalling in cancer, with particular relevance to evidence supporting a role in testicular germ cell tumours (TGCTs). Despite the clear preclinical rationale for targeting the IGF axis in cancer, there has been a lack of progress in identifying which patients may benefit from such therapy. Future employment of agents targeting the IGF pathway is expected to concentrate on their use in combination with other treatments to prevent resistance and exploit their potential as chemo‐ and radiosensitizers.

show abstract

“…It was found that a combined treatment with selective ER modulator and IGF1R inhibitor was significantly more effective than using a single-agent treatment on different ER + and HER2 +/− cell lines with variable IGF1R intensity. This effect was due to the induction of cell-cycle arrest (11).…”

Section: Discussionmentioning

confidence: 99%

“…The increase of IGF1R in BC cells was found to be due to an increase in IGF1 that is regulated by estradiol through synergistically stimulating cancer cell proliferation and suppressing several tumor-suppressor genes (11). Whereas it has been shown that there is a cross talk between estrogen receptor positivity (ER + ) and IGF1R expression owing to up-regulation of IGF1R transcription through activating ER complexes (12).…”

mentioning

confidence: 99%

Correlation of Insulin-like Growth Factor 1 Receptor Expression With Different Molecular Subtypes of Breast Cancer in the UAE

et al. 2020

View full text Add to dashboard Cite

Background: Insulin-like growth factor 1 receptor (IGF1R) activation triggers multiple signaling pathways involved in proliferation and anti-apoptosis in breast cancer (BC). Materials and Methods: Immunohistochemistry for IGF1R was performed on 50 BC cases; expression was assessed for staining intensity and localization pattern (mixed, membranous, and cytoplasmic) which was correlated to hormone receptor status. Results: Of estrogen receptorpositive (ER + ) cases, 97.2% were IGF1R + (48.6% mixed, 43.2% membranous, and 5.4% cytoplasmic pattern) compared to ER − cases (38.5%, 7.7% and 30.8%, respectively) (p=0.003). In progesterone receptor-positive (PR + ) cases, 97.2% were IGF1R + , (47.2%, 41.7% and 8.3%, respectively) compared to PR − ones (42.9%, 14.3% and 21.4%, respectively) (p=0.036). For human epidermal growth factor receptor 2-negative (HER2 − ) cases, 88.8% were IGF1R + (44.4%, 8.3% and 36.1%, respectively). All HER2 + cases were IGF1R + (71.4%, 7.1% and 21.4%, respectively) (p=0.015). In conclusion, hormone receptor-positive HER2 − cases showed membranous and mixed IGF1R localization. However, hormone receptor-negative and HER2 + showed cytoplasmic or diminished IGF1R expression. Conclusion: These luminal subtypes may benefit from targeted IGFR therapy in the future.

show abstract

Dual inhibition of IGF1R and ER enhances response to trastuzumab in HER2 positive breast cancer cells

Cited by 26 publications

References 35 publications

Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies

Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies

IGF signalling in germ cells and testicular germ cell tumours: roles and therapeutic approaches

Correlation of Insulin-like Growth Factor 1 Receptor Expression With Different Molecular Subtypes of Breast Cancer in the UAE

Contact Info

Product

Resources

About