The puzzle of chemotherapy resistance

What is a breakthrough in cancer research? It is a new piece of a puzzle made up of a million pieces. It may, however, be a piece that allows a picture to start emerging – one that lets us see the shape of the next piece needed to fill in more of the puzzle, or start making changes to rearrange the picture from one of cancerous growth to one of normalcy.

The Institute’s Prof. Yosef Yarden’s recent research provides a vital piece for the puzzle of resistance – how cancer cells, especially those in recurring cancers, stop responding to chemotherapy. His answer is specific to a kind of lung cancer, one that has a certain mutation in the gene for a growth receptor on the cell’s outer membrane. So his findings point to the need for both a personalized approach to treating cancer and a new general approach to understanding the lengths that certain cancer cells will go to in order to keep dividing and spreading.

The particular puzzle was that the chemotherapy used to treat these lung cancers almost always sends them into what appears to be complete remission. But they invariably come back, often with a second mutation in the same receptor; and the new cancer is not only resistant to the original chemotherapy, it is also resistant to a second drug that should, by all scientific reckoning, block the re-mutated growth receptor and thus stop the cancer’s spread.

Lung cancer cells (green) cultured together with normal lung cells (red). The triple-antibody combination EGFR, HER2 and HER3 strongly impairs the survival of tumor cells while sparing normal cells. Modified confocal microscopy image: Maicol Mancini, lab of Prof. Yosef Yarden

Yarden and his group found that the resistant cancer cells had actually rewired a main internal communications line, ultimately putting several “sibling” receptors on the cell’s outer surface. These siblings can take in the growth signal but are impervious to the drugs that block the original signal.

With this piece of the puzzle in hand, he and his team were able to design antibodies to block the two other receptors, and they applied these together with the original antibody that “should have worked.” This “triple treatment” was very effective against resistant lung cancers – in lab dishes and in mice.

Since lung cancer is the leading cause of cancer death, worldwide, this is a little piece of the puzzle that could, conceivably, have pretty large implications in the future. But not just for lung cancer: The emerging picture, say Yarden, is one in which drugs that target just one receptor, for example, the cancer cell’s growth receptor, can activate a chain reaction that turns the cell resistant and possibly even more ready to divide and spread than before. Yarden had previously shown in collaboration with Prof. Michael Sela of the Institute, that certain breast cancers arising from specific mutations can be treated with a combination of receptor-blocking drugs. In other words, this mechanism of chemotherapy resistance is likely to be present in many cancers, suggesting that more than a few more pieces of the puzzle might now be within reach.