Breast cancer (illustrative photo).
(photo credit: INGIMAGE)
Lung cancer – which annually kills some 1.6 million people worldwide – often recurs because the tumor is resistant to the chemotherapy and other drugs that originally drove it into remission. According to new research by Prof. Yosef Yarden of the Weizmann Institute of Science in Rehovot, a new strategy involving a three-pronged approach could keep an aggressive form of lung cancer from returning.
The research, said Yarden, arose out of some confusing clinical trial results. One class of relatively common lung cancers, which carry a particular mutation in a receptor on the cell membrane called EGFR, can be treated with a sort of “wonder drug.” This medication keeps a growth signal from getting into the cell, thus preventing the deadly progression and spread of the cancer. But within a year, those with this mutation almost always experience new cancer growth, usually as a result of a second EGFR mutation.
To prevent this from happening, researchers had tried to administer another drug, an antibody that is today used to treat colorectal cancer. This drug also obstructs the passing of the growth signal to the EGFR. Even though the antibody drug should have been able to effectively block the growth signal to the EGFR receptors – including those generated by the second mutation – clinical trials of this drug for lung cancer did not produce the expected result.
“This finding ran counter to everything we knew about the way tumors develop resistance,” said Yarden, who with his student, Maicol Mancini, just published findings in the journal Science Signaling.
“The blocked receptor has ‘siblings’ – other receptors that can step up to do the job,” said Yarden. Indeed, the team found that when the EGFR continued to be blocked, one of the cell’s communication networks was rerouted, causing the siblings to appear on the cell membrane instead of the original receptor.
The finely tuned antibody did not block these, and thus the cancer cells once again became active.
The researchers uncovered the chain of protein communication in the new network that ultimately leads to the appearance of the sibling growth receptors. This new network may overcompensate for the lack of the original receptor, making it even worse than the original.
Once the researchers discovered how the blockade was breached, they set out to erect a better line of defense. Yarden and his team created new monoclonal antibodies that could target the two main growth receptor siblings, named HER2 (the target of the breast cancer drug Herceptin) and HER3.
The idea was to give all three antibodies together – the two new ones and the original anti-EGFR antibody – to preempt resistance to the treatment. Indeed, in isolated cancer cells, applying the triple treatment prevented them from completing the rewiring necessary to continue receiving growth signals.
Next, the team tried the three-pronged approach on mice with lung cancer that had the secondary, resistance mutation. In these mice, the tumor growth was almost completely arrested. More important, further research showed that this treatment reined in the growth of the tumor while leaving healthy cells alone.
Although much more research is needed before the triple-treatment approach reaches clinics, Yarden said he hopes it will change not only the treatment protocol for lung cancer but also understanding of the mechanisms of drug resistance.
“Treatment by blocking a single target can cause a feedback loop that ultimately leads to a resurgence of the cancer,” he said. “If we can predict how the cancer cell will react when we block the growth signals it needs to continue proliferating, we can take preemptive steps to prevent this from happening.”
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