Drug Combination Could Offer Therapy for Treatment-Resistant Breast Cancer

The average woman has a 13% risk of developing breast cancer in the US at some point in her life and every year in the US, there are around 240,000 cases of breast cancer in women and 2,100 cases in men. In a study led by UT Southwestern Medical Center researchers, Marín et al. identify a specific combination of existing cancer drugs that can target breast cancer cells that were previously resistant to treatment. The findings were published in the journal Cancer Research.

Targeting HER2-mutant breast cancer cells

Mutations in HER2 are present in many forms of metastatic breast cancers and the gene has become a popular target in cancer therapy. HER2 is a member of the ERBB receptor tyrosine kinase family, which includes EGFR, HER3 and HER4. Most HER2 mutations lead to overexpression of the protein and drive cancer growth. The irreversible pan-HER tyrosine kinase inhibitor (TKI) neratinib has demonstrated efficacy in treating breast cancer in preclinical models of HER2-mutant breast cancer, as well as in clinical trials. However, responses to neratinib are often not long-lasting and breast cancer lines that develop secondary mutations in HER2 often end up showing resistance to neratinib. Marín et al. wanted to improve understanding of the role that secondary HER2 mutations play in treatment-resistant breast cancer and find ways to effectively target double-mutant cancerous cells.

Characterizing double-mutant HER2 cells and developing a therapeutic solution

Marín et al. utilized MCF10A cells, a healthy breast cell line, and engineered them to contain various HER2 mutations (either single or double mutations). They assessed the impact of neratinib on each cell line’s viability and proliferation. Additionally, they used the MMPBSA approach to estimate the binding affinity between HER2 and neratinib and used computational structural analysis to conceptualize the active and inactive state of HER2. The team also wanted to assess the impacts of other TKIs on the varying cancerous phenotypes, so they screened nine common HER2-targeting TKIs individually on the cells to assess the resistance of all cell lines. Then, they proceeded to test combinations of these drugs with inhibitors of other kinases that were overexpressed in HER2 double-mutant cells.

The key findings of the study were:

• Acquired secondary HER2 mutations enhanced phosphorylation of AKT, ERK and S6, all of which are signaling molecules downstream of HER2.
• Neratinib treatment was able to suppress the growth of all HER2 single-mutant cells, but none of the HER2 double-mutant cells.
• Computational modeling suggested that secondary HER2 mutations stabilized the HER2 active state and reduced neratinib binding affinity.
• Double-mutant cells were resistant to all HER2 TKIs, except for mobocertinib and poziotinib.
• Cells with double HER2 mutations had greater MEK/ERK signaling, which was successfully blocked by combined treatment with HER2 and MEK inhibitors.

Using a combination of drugs to combat treatment-resistant breast cancer

By studying cell lines with a variety of HER2 mutations, Marín et al. were able to improve characterization of the role of the HER2 mutations in treatment-resistant breast cancer. It is already known that most mutations in HER2 can be targeted via TKIs, but often their efficacy becomes limited when there are secondary mutations in the gene. Because of this, Marín’s team was interested in understanding the role that secondary mutations play in the resistance of breast cancer cells to TKIs. They found that acquired secondary mutations in HER2 resulted in increased phosphorylation of AKT, ERK and S6, all of which are signaling molecules downstream of HER2 and play a role in the propagation of the cancerous pathway. As expected, they also found that neratinib was able to target and control growth of HER2 single-mutant cells, but was unable to stop the proliferation of HER2 double-mutant cells. In fact, HER2 double-mutant cells were resistant to all HER2 TKIs, with the exception of mobocertinib and poziotinib. They found that this was because HER2 mutations played a role in stabilizing the HER2 active state and reduced the binding affinity of neratinib to HER2. Additionally, they found that double-mutant cells had greater than normal MEK/ERK signaling. To combat this issue, Marín et al. used a combined treatment of HER2 and MEK inhibitors, which successfully blocked the growth of these double-mutant cells.

Resistance to drugs remains one of the key problems in current cancer therapeutics. Among patients who have breast cancer, HER2 is one of the most common genes that contains a mutation, which is why targeting the product of this gene in therapy has become important. The presence of multiple mutations in HER2 has made it difficult to develop treatments, but Marín et al demonstrated the potential that combinations of drugs could hold in treating HER2-mutant breast cancer. The individual drugs already exist, but now the challenge lies in establishing the best combinations that enable them to be used safely and effectively. Some of the concentrations of inhibitors that were used in this study were high and would not be safe in humans, so determining the appropriate equivalents for clinical trials would be an important next step.

Implementation in the clinic

Using a combination of HER2 and MEK inhibitors holds potential in the clinic if a safe and efficacious dose can be established. Breast cancer has affected, and continues to affect, the lives of thousands of people every year, and creating novel solutions using existing materials has the potential to be a valuable therapy in the future of cancer care.

Reference: Marín A, Mamun AA, Patel H, et al. Acquired secondary HER2 mutations enhance HER2/MAPK signaling and promote resistance to HER2 kinase inhibition in breast cancer. Cancer Res. 2023;83(18):3145-3158. doi:10.1158/0008-5472.CAN-22-3617

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