From the Guidelines
Cancer genes that exhibit resistance to chemotherapy include BRCA1/BRCA2, TP53, and CCNE1, among others, which can lead to reduced effectiveness of platinum-based treatments and other chemotherapies. The development of resistance to chemotherapy is a complex process involving various genetic and molecular mechanisms. According to 1, germline or somatic mutations in HR genes, including BRCA1 and BRCA2, can contribute to genomic instability and resistance to platinum-based chemotherapy. Additionally, mutations in other genes such as TP53 and CCNE1 can also play a role in chemoresistance.
Some key points to consider:
- BRCA1/BRCA2 mutations can lead to increased resistance to chemotherapy, despite initial sensitivity 1
- TP53 mutations can prevent cancer cells from undergoing apoptosis when damaged by chemotherapy 1
- CCNE1 amplification has been associated with chemoresistance and poor overall survival in ovarian cancer patients 1
- Other genes, such as ABCB1 (MDR1) and MGMT, can also contribute to chemoresistance by pumping chemotherapy drugs out of cancer cells or repairing DNA damage caused by alkylating agents
To address chemoresistance, oncologists may employ combination therapies using drugs with different mechanisms of action, such as pairing taxanes with platinum agents. PARP inhibitors like olaparib may overcome resistance in BRCA-mutated cancers, while tyrosine kinase inhibitors target specific mutations. Understanding a tumor's genetic profile through comprehensive genomic testing is increasingly important for selecting effective treatment strategies that can overcome or bypass these resistance mechanisms 1.
The most recent and highest quality study, 1, highlights the importance of CCNE1 amplification as a predictive factor of tumor primary chemosensitivity, and suggests that additional data on larger datasets are needed to understand the potential use of this biomarker for ovarian cancer management adjustment.
Overall, the development of resistance to chemotherapy is a complex process involving various genetic and molecular mechanisms, and a comprehensive understanding of these mechanisms is essential for selecting effective treatment strategies.
From the Research
Cancer Genes and Chemotherapy Resistance
The relationship between cancer genes and chemotherapy resistance is complex, involving various mechanisms that limit the effectiveness of chemotherapies. Some of the key mechanisms include:
- Increased drug inactivation, as mentioned in 2
- Drug efflux from cancer cells, discussed in 2, 3
- Enhanced repair of chemotherapy-induced damage, highlighted in 2, 3, 4
- Activation of pro-survival pathways and inactivation of cell death pathways, noted in 2, 5, 4
Specific Mechanisms of Resistance
Several specific mechanisms have been identified, including:
- Alterations in drug targets and signaling transduction molecules, as described in 3, 4
- Increased drug export, mentioned in 3
- Deregulation of programmed cell death, including apoptosis and autophagy, discussed in 3, 4
- Epigenetic changes, noted in 4, 6
- Gene amplification, mentioned in 6
Genetic and Epigenetic Factors
Genetic and epigenetic changes play a significant role in cancer cell resistance to chemotherapy, including:
- Modifications in nucleotide synthesis enzymes, microtubule composition, and topoisomerase activity, as described in 4
- Stemness properties of cancer cells and components of the tumor stroma, noted in 4
- Hypoxia, mentioned in 4
- Individual genetic differences, especially in tumoral somatic cells, discussed in 6