Why Cancer Drugs Stop Working

ALK positive lung cancer becoming resistant to crizotinib

(RxWiki News) A common story in cancer treatment is of specialized drugs that work great initially, but over time the cancer becomes resistant to the drug. Finding out why this happens has become paramount for scientists.

In the first study of its kind, researchers working with the drug Xalkori (crizotinib), a type of inhibitor that is specific for anaplastic lymphoma kinase (ALK) positive lung cancer studied precisely how patients’ cancers became immune to the treatment.

"Ask your oncologist about chemotherapy resistance."

In research conducted at the University of Colorado Cancer Center, fourteen patients with ALK positive non-small cell lung cancer whose cancer had started to grow on Xalkori had their cancers re-biopsied and re-analyzed compared to before they had started on the Xalkori.

Patients who are (ALK) positive usually achieve excellent results in terms of cancer shrinkage from Xalkori. Unfortunately resistance to Xalkori usually takes place at about the eleven month mark.

Ross Camidge, M.D., Ph.D, the director of the lung cancer clinical program at University of Colorado Hospital (UCH) explained that "What we found was both enlightening and challenging at the same time."

“ALK positive lung cancer starts off as a gene rearrangement that turns on the cancer. What we found was that cancers became resistant to the crizotinib in two main ways. Either they altered the ALK gene, changing the number of copies of it, or getting new mutations in it, so that the drug was less effective. Alternatively, they dialed up a completely different molecular driver of the cancer, either co-existing in the same cells as the ALK change, or spinning off independent clones that were completely ALK negative,” Camidge said.

Finding out the mechanism cancers use to evade treatment is huge, because when the cancer changes, without knowing what happened, doctors can only guess at what the next treatment should be.

Knowing that an ALK positive non-small cell lung cancer became resistant through changing the ALK gene suggests that a stronger version of an ALK inhibitor should be effective.

But if something else has started to drive the cancer then different drugs, probably in combination with an ALK inhibitor may be a better approach.

Based on his research, Dr. Camidge said, "The changes that we documented show us once again that we can't treat cancer as one disease. Lung cancer is as individual as our patients."

Results were published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR).

The study was supported by grants from the Boettcher Foundation, and University of Colorado's Lung Cancer Specialized Program of Research Excellence (SPORE).

Review Date: 
February 6, 2012