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New generation lung cancer drugs have been effective in a large number of patients, but in the space of about a year, patients tend to develop resistance to therapy. Researchers at the Weizmann Institute of Science, working with physicians, conducted a study in mice, in which they used existing drugs in a new combination to help crush the potential resistance to treatment. Their results were published recently in the journal Clinical Cancer Research
Lung cancer is the most common cause of cancer death, accounting for about one-fifth of all cancer deaths worldwide. New drugs treat certain subtypes of this cancer by targeting the genetic mutations characteristic of each subtype.
In about 12% of lung cancer patients, mostly non-smokers, the malignancy is due to mutation. gene called EGFR. This gene encodes a receptor that is integrated in the cell membrane, protruding in both directions: its "head", the outer part of the cell surface, binds to a growth factor that transmits a growth signal to the cell; the "legs", the inner part inside the cell, functions as an enzyme that further transmits the signal to the cell nucleus. The EGFR growth message causes the cell to divide, which normally has a good effect – for example, to help the tissues heal – but a mutation on the inner part of the receptor can cause an uncontrolled division of the cell, leading to cancer
The EGFR mutation can be aided by small molecules called kinase inhibitors, which block the mutation, preventing the EGFR from generating an uncontrolled division signal. These drugs work much better than chemotherapy: they are more effective and cause fewer side effects, and they can be taken as a pill rather than by injection. The problem is that within 10 to 14 months, many patients develop a secondary mutation in the EGFR. This causes the relapse of their tumors as it allows the EGFR to bypbad the kinase inhibitor
In 2015, a new kinase inhibitor known under the trade name Tagrisso, which blocks this second mutation, has has been approved for clinical use when the lung tumor begins to grow again. Tagrisso helps, but usually not for long. Again, in a period of 10 to 14 months, a third mutation or other alterations appear in the EGFR gene, causing another relapse.
"This is of course a nightmare for patients, their families and doctors". the Department of Biological Regulation. "We have now developed a new approach that works on mice and can help relieve this frustrating situation if our method proves to work in humans."
In collaboration with doctors at Chaim Sheba Medical Center in Tel Hashomer, Israel, Yarden's team tried a combination therapy. Mice implanted with human lung cancer cells received Tagrisso and a drug that blocks EGFR on the cell surface. This drug was Erbitux, an antibody that binds to the protruding outer part of the EGFR, preventing the cell from receiving the growth message. The Tagrisso that has been administered to them works inside the cell, preventing the internal part of EGFR, the kinase promoting growth, to relay the growth signal.
This original combined therapy attempt was unsuccessful, probably because the EGFR is blocked. On the surface of the cell, it uses a close "parent", a receptor called HER2, to appear on the cell membrane. Thus, in the new study, the researchers gave the mice a triple combination therapy, which apart from Tagrisso included two antibodies instead of one: Erbitux and a drug called Herceptin, which blocks HER2.
This time the approach worked. The tumors substantially shrink and do not regrow as long as the mice receive the triple combination treatment. The use of this approach in human patients should be facilitated by the fact that both antibodies are already approved for use against other cancers: Erbitux is used in colorectal cancer and Herceptin, in cancer bad.
The new combination therapy can help prolong the lives of many thousands of lung cancer patients who are currently developing resistance to kinase inhibitors, "says Yarden,
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