Resistance to Targeted Therapies in Breast Cancer
Sofia Braga1,2
1José de Mello Saúde, Avenida Do Forte Edifício Suécia III, Piso 2, Carnaxide, Lisbon, Portugal. Sofia.Braga@jmellosaude.pt.
Abstract:
Seventy five percent of all breast cancer (BC) patients express estrogen receptor (ER) but a quarter to half of patients with ER positive BC relapse on ET (endocrine therapy), tamoxifen, aromatase inhibitors (AIs), surgical castration, amongst other treatment strategies. ER positive BC at relapse loses ER expression in 20 % of cases and reduces quantitative ER expression most of the time. ER is not the only survival pathway driving ER positive BC and escape pathways intrinsic or acquired are activated during ET. This overview gives an account of ligand-independent ER activation, namely by receptor networks cross talk, and by the various genomic factors and mechanisms leading to ET response failure. Also the mechanisms of Her1 and Her2 inhibition resistance are dealt within this overview, along with the therapeutic indications and limitations of tyrosine kinase inhibitors, PARP inhibitors, PI3K/AKT/mTOR inhibitors, RAS/RAF/MEK/ERK/MAPK inhibitors, and antiangiogenic drugs. In spite of the many advances in controlling the division of BC cells and the progression of BC tumors these still remain the main cause of death among women in age range of 20-50 years requiring even more efforts in new therapeutic approaches besides the drugs within the scope of the overview.
Insights
Many estrogen receptor-positive breast cancer patients relapse on endocrine therapy. This review explores mechanisms of treatment resistance and discusses targeted therapies, highlighting the need for novel approaches.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Estrogen receptor (ER)-positive breast cancer (BC) affects 75% of patients.
- A significant proportion of ER-positive BC patients relapse despite endocrine therapy (ET).
- ER expression can be lost or reduced at relapse, indicating complex resistance mechanisms.
Purpose of the Study:
- To review mechanisms of endocrine therapy resistance in ER-positive breast cancer.
- To explore ligand-independent ER activation and genomic factors contributing to treatment failure.
- To discuss resistance to HER1/HER2 inhibition and limitations of targeted therapies.
Main Methods:
- Literature review of mechanisms driving endocrine therapy resistance.
- Analysis of genomic factors and receptor crosstalk in ER-positive BC.
- Overview of resistance pathways to targeted therapies including tyrosine kinase inhibitors, PARP inhibitors, PI3K/AKT/mTOR inhibitors, RAS/RAF/MEK/ERK/MAPK inhibitors, and antiangiogenic drugs.
Main Results:
- Ligand-independent ER activation and genomic alterations are key to ET resistance.
- Acquired or intrinsic escape pathways contribute to treatment failure.
- Resistance to HER1/HER2 inhibition involves complex signaling networks.
Conclusions:
- Understanding resistance mechanisms is crucial for improving ER-positive breast cancer outcomes.
- Targeted therapies show promise but have limitations, necessitating further research.
- Novel therapeutic strategies are required to overcome treatment resistance and reduce BC mortality.
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