Final Report Summary - OVER-HER2 (OVErcoming Resistance to anti-HER2 therapy)
Our ERC project aims to study the molecular mechanisms involved in anti-HER2 therapy resistance and to propose therapeutic strategies to overcome acquired resistance.
HER2 is a membrane receptor tyrosine kinase overexpressed in 30% of breast tumors and results in an aggressive clinical course. Anti-HER2 therapies including monoclonal antibodies (trastuzumab) and small-molecule tyrosine kinase inhibitors (lapatinib) are active and lead to improved survival of patients with HER2 overexpressing breast cancer. However, the emergence of primary or acquired resistance to these agents limits their efficacy. We had previously identified mechanisms of resistance to anti-HER2 therapies such as the co-expression of a truncated form of HER2 that correlates with trastuzumab resistance or the presence of downstream oncogenic mutations of PI3K or PTEN loss. An additional mechanism of resistant has been identified, namely the amplification of cyclin E. To overcome anti-HER2 therapy resistance we have tested several therapeutic strategies, such as combinations of different anti-HER2 compounds and the use of other agents targeting downstream / parallel pathways. Among the novel targeted therapies, we used PI3K, Akt, CDK2 and Hsp90 inhibitors.
We have developed a clinically relevant model to test the activity of anticancer therapeutic strategies and to study biomarkers of response and resistance. These models represent a step further towards a representation of the cancer heterogeneity in terms of genetics and tissue compartments, compared to established cell lines or genetically modified mouse models. The ERC grant has allowed us to develop this long-term asset, along with a collaborative team that joins translational and clinical researchers working together in a unique Institution.
Our work has enabled us to further identify subtypes of sensitivity to PI3K-pathway inhibitors and to dissect the activity and biomarkers of response to these agents and thereof combination of anticancer agents. Our results have been valuable for the decisions of relevant clinical trials in providing pharmacodynamic biomarkers and proposing predictive biomarkers of response.
HER2 is a membrane receptor tyrosine kinase overexpressed in 30% of breast tumors and results in an aggressive clinical course. Anti-HER2 therapies including monoclonal antibodies (trastuzumab) and small-molecule tyrosine kinase inhibitors (lapatinib) are active and lead to improved survival of patients with HER2 overexpressing breast cancer. However, the emergence of primary or acquired resistance to these agents limits their efficacy. We had previously identified mechanisms of resistance to anti-HER2 therapies such as the co-expression of a truncated form of HER2 that correlates with trastuzumab resistance or the presence of downstream oncogenic mutations of PI3K or PTEN loss. An additional mechanism of resistant has been identified, namely the amplification of cyclin E. To overcome anti-HER2 therapy resistance we have tested several therapeutic strategies, such as combinations of different anti-HER2 compounds and the use of other agents targeting downstream / parallel pathways. Among the novel targeted therapies, we used PI3K, Akt, CDK2 and Hsp90 inhibitors.
We have developed a clinically relevant model to test the activity of anticancer therapeutic strategies and to study biomarkers of response and resistance. These models represent a step further towards a representation of the cancer heterogeneity in terms of genetics and tissue compartments, compared to established cell lines or genetically modified mouse models. The ERC grant has allowed us to develop this long-term asset, along with a collaborative team that joins translational and clinical researchers working together in a unique Institution.
Our work has enabled us to further identify subtypes of sensitivity to PI3K-pathway inhibitors and to dissect the activity and biomarkers of response to these agents and thereof combination of anticancer agents. Our results have been valuable for the decisions of relevant clinical trials in providing pharmacodynamic biomarkers and proposing predictive biomarkers of response.