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Published on: October 1, 2007
Development of a personalized therapeutic strategy for ERBB-gene-mutated cancers
Malgorzata Milewska1, Mattia Cremona1, Clare Morgan1
1Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, ERC Smurfit Building, Dublin 9 Ireland.
Background:
The application of genomic technologies to patient tumor samples identified groups of signaling pathways which acquire activating mutations. Some cancers are dependent on these mutations and the aberrant proteins resulting from these mutations can be targeted by novel drugs which can eradicate the cancer.
Methods:
We used www.cbioportal.org to determine the frequency of ERBB mutations in solid tumors. We then determined the sensitivity of a panel of cell lines to clinically available PI3K inhibitors. Using proliferation and apoptosis assays as well as functional interrogation with reverse phase protein arrays we demonstrated the impact of targeting ERBB-mutant cancers with the combination of a PI3K inhibitor and the pan-HER family inhibitor afatinib.
Results:
In over 14,000 patients we found that 12% of their tumors have an ERBB family gene mutation (EGFR, ERBB2, ERBB3 and ERBB4). In cancers not commonly associated with HER family protein overexpression, such as ovarian, endometrial, melanoma and head and neck cancers (n = 2116), we found that ERBB family mutations are enriched, occurring at rates from 14% to 34% and commonly co-occur with PIK3CA mutations. Importantly, we demonstrate that ERBB family mutant cancers are sensitive to treatment with PI3K inhibitors. Finally we show that the combination of afatinib and copanlisib represents a novel therapeutic strategy for patients whose cancers harbor both ERBB family and PIK3CA mutation.
Conclusions:
We demonstrate that ERBB family mutations are common in cancers not associated with overexpression or amplification of HER family proteins. These ERBB family mutant cancers are sensitive to treatment with PI3K inhibitors, and when combined with pan-HER inhibitors have synergistic antiproliferative effects.
Insights
ERBB family mutations are common in many cancers and can be targeted by PI3K inhibitors. Combining PI3K inhibitors with afatinib offers a novel therapeutic strategy for ERBB-mutant cancers.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Genomic technologies reveal signaling pathway mutations in cancer.
- Targeting aberrant proteins from activating mutations offers novel cancer eradication strategies.
Purpose of the Study:
- Determine ERBB mutation frequency in solid tumors.
- Assess sensitivity of ERBB-mutant cell lines to PI3K inhibitors.
- Evaluate combination therapy of PI3K and pan-HER inhibitors.
Main Methods:
- Utilized cBioPortal for mutation frequency analysis.
- Conducted proliferation and apoptosis assays.
- Performed reverse phase protein array analysis.
Main Results:
- ERBB family mutations found in 12% of over 14,000 tumors.
- Mutations enriched in ovarian, endometrial, melanoma, and head and neck cancers (14-34%).
- ERBB-mutant cancers sensitive to PI3K inhibitors; combination therapy shows synergy.
Conclusions:
- ERBB family mutations are prevalent in cancers lacking HER protein overexpression.
- ERBB-mutant cancers are sensitive to PI3K inhibitors.
- Combination of afatinib and copanlisib is a potential therapeutic strategy for ERBB and PIK3CA mutant cancers.
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