Neratinib defeats the Ras genes notorious for causing cancer
European Pharmaceutical Review
A new study has shown the recently approved breast cancer drug neratinib can block the function of the Ras genes — H-Ras, K-Ras and N-Ras — which are among the first to be linked to cancer development, and as well as several other oncogenes through an unexpected process.
The study set out to determine whether neratinib could be utilised, alone or in combination with other agents, to kill non-small cell lung cancer (NSCLC) cells that had become resistant to the drug afatinib. Both afatinib and neratinib were designed to inhibit EGFR and HER2 kinases, which are enzymes that regulate cancer cell growth and chemotherapy resistance.
When we looked at the cells under the microscope, we saw neratinib, but not afatinib, causing large vesicles to form next to the cell’s outer membrane.
Afatinib is similar to neratinib, however, neratinib irreversibly attaches itself onto EGFR and HER2. This attachment permanently blocks the function of the receptors, causing the cell to target them for degradation. Dr
“When we looked at the cells under the microscope, we saw neratinib, but not afatinib, causing large vesicles to form next to the cell’s outer membrane. In these vesicles, we saw the EGFR and HER2 receptors being broken down, but we also saw our negative control receptor, c-MET,” said
We found that neratinib triggers a seismic event in the plasma membrane
The vesicles the researchers saw were part of a process known as autophagy, a natural mechanism that breaks down and recycles unwanted cellular components. Because it is a membrane protein, the scientists turned their attention to Ras. And because of evidence that the common seizure medication valproic acid can influence the regulation of autophagy, they decided to test whether it could synergize with neratinib to further block the actions of Ras.
In addition to the afatinib-resistant NSCLC cells, the researchers tested the neratinib and valproic acid combination on cell lines derived from human pancreatic and ovarian cancers containing K-Ras mutations and N-Ras mutations, respectively.
“We found that neratinib triggers a seismic event in the plasma membrane where not only are ERBB family receptors such as EGFF and HER2 degraded, but other related receptors in the membrane are brought along for the ride,” said
We are excited about the potential of neratinib to treat a variety of cancers.
In addition, the study uncovered other exciting clinical possibilities for neratinib. The scientists tested neratinib in animal models of breast cancer and found that it enhanced the effectiveness of previously established drug combinations, including pemetrexed and sorafenib, which is currently being tested in a phase 2 clinical trial at Massey for the treatment of triple negative breast cancer.
“We are excited about the potential of neratinib to treat a variety of cancers and complement existing therapies,” said
The study has been published in the journal Oncotarget.