In acute lymphoblastic leukemia, immature white blood cells -- stained purple here -- proliferate in the marrow, crowding out normal cells and spreading to other organs. It's fatal in a few weeks without treatment.IMAGE: WIKIMEDIA COMMONS, USER VASHIDONSKyrosine kinase inhibitors (TKIs) quell unregulated cell growth and are commonly used to treat cancer, but many tumors develop resistance to the therapy. New research published today in Nature identifies a pathway that keeps the cancer cells alive long enough to evolve such resistance, and shows that inhibiting this pathway in mice with acute lymphoblastic leukemia (ALL) can prevent treatment evasion and cancer reemergence.

"This is a very important article showing a novel mechanism for ALL resistance to TKI therapy," leukemia immunologist Meir Wetzler of the Roswell Park Cancer Institute, who was not involved in the research, wrote in an email to The Scientist. "It holds promise for novel treatment...

Many cancers -- leukemia, breast, lung, malignant melanoma, to name a few -- contain mutations in tyrosine kinase enzymes that result in unregulated cell growth. A major breakthrough in cancer treatment was the development of Imatinib, marketed as Gleevec, which inhibits these tyrosine kinases, halting cancer growth. However, the cells do not die, but persist in a quiescent state, allowing some cancerous cells to evolve resistance to the drug and reemerge.

Oncologists then try different TKIs to fight the cancer but "it's a losing battle," said leukemia geneticist Markus Muschen of the University of California San Francisco. "[The cancer] will continue to evolve resistant subclones and ultimately evade all of them. These patients don't have a good prognosis."

While much research focuses on developing new, stronger TKIs, Muschen and his colleagues decided to take a different approach -- hamper the cancer's ability to evolve resistance in the first place. The researchers focused on ALL, a particularly fatal cancer that is responsible for 70 percent of childhood leukemia and commonly evolves TKI resistance. Comparing gene expression analysis among samples from 150 ALL patients, they found that one gene was consistently upregulated: BCL6, which codes for a protein that is frequently mutated in B-cell lymphomas -- a cancer of the immune system.

"Our first thought was that BCL6 is not supposed to be there," said Muschen. But a year later, they verified the finding, identifying the functional protein in ALL cells.

BCL6 is activated in B-lymphocytes when antibody molecules are being built, a process that involves breaking and rearranging DNA to create a variety of antigen-binding sites. Broken DNA typically signals p53-mediated DNA repair pathways or, if the damage is beyond repair, apoptosis, but BCL6 blocks the production of p53 in B-cells so that antibody molecules can be constructed. It's a double-edged sword, however, as p53 is also a major anti-cancer molecule, and its blockage can facilitate cancerous growth or prevent cancer cells from being killed.

It appeared, Muschen said, that after treatment with TKIs, cancer cells enter "emergency mode in which they upregulate BCL6 and shut down p53 function," said Muschen. "These cells don't divide anymore but they cannot die either."

Sure enough, when the researchers treated mice with human-derived ALL with just TKIs, they saw the same effect observed in human patients: the cancer went dormant at first, but eventually returned, killing all the mice within about 3 months. But when these mice were treated with TKIs and a BCL6 inhibitor, seven of eight mice were still alive nearly 5 months later.

This "double-pronged approach" of both killing the cancer cells and blocking their ability to evolve resistance is necessary, said Muschen. "You must attack leukemia from two sides: attack proliferation mode and also come from the opposite angle and cut off the retreat pathway."

This inhibitor, developed by cancer pharmacologist Ari Melnick of Weill Cornell Medical College to treat B-cell lymphoma, binds to BCL6, preventing it from blocking p53 signaling. However, this drug is prohibitively expensive, so Muschen and Melnick are working under a $3.6 million grant from the California Institute for Regenerative Medicine to develop a cheaper small-molecule inhibitor, which they hope to test in clinical trials next year.

"It is certainly interesting," said clinical oncologist Elias Jabbour of the MD Anderson Cancer Center, who was not involved in the research, but "it's always hard to translate findings from a cell line into clinical reality. I wouldn't even dare speculating that this has any clinical value in the foreseeable future."

C. Duy et al., "BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition," Nature 473: 384-8, 2011.

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