Cancer researchers have discovered a potential way to make targeted therapy drugs more effective and longer lasting for people with acute myeloid leukemia, or AML.

The scientists showed how it is possible to eliminate leukemia cells lingering after initial therapy before they can bounce back with genetic mutations for drug resistance.

“Understanding the biology of early resistance may offer new opportunities to prevent or delay late resistance and improve clinical outcomes,” said first author Sunil Joshi, Ph.D., a medical student in the OHSU School of Medicine. The paper describing the findings is published in Cancer Cell.

AML is a fast-advancing blood cancer and one of the most difficult to treat. The need for better therapies is critical. Each year, more than 20,000 Americans are diagnosed with AML and more than 10,000 die from it. The five-year-survival rate is around 30%, versus rates of 70% and higher in other common forms of leukemia.

New targeted therapy drugs have fallen short of their promise because the cancer can quickly evolve to become resistant to treatment. Gilteritinib, for example, is a targeted drug that blocks a pivotal enzyme called FLT3, which is typically altered in AML to drive cancer growth. Gilteritinib is very effective at stopping the cancer – but not for long. Some leukemia cells persist in the bone marrow and over time these early-resistant cells acquire genetic mutations that enable them to overcome the targeted therapy and continue multiplying. This late resistance limits how long the treatment can help patients survive.

Joshi and colleagues tackled the problem by tracking, in painstaking detail, changes in leukemia cells grown in the lab as the cells developed to an advanced resistant state.

“When thinking of drug resistance in cancer, we associate it with the acquisition of genetic mutations in tumor cells,” Joshi said. “Results of our work bring to light other biological processes that contribute to explaining why certain cancer cells survive therapy while others do not.” He recently completed his doctoral degree under the mentorship of Brian Druker, M.D., Elie Traer, M.D., Ph.D., and Cristina Tognon, Ph.D., who are co-authors of the work.

‘This concept should be clinically tested and holds promise for improving outcomes in AML patients’

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Bone marrow, where leukemia cells originate, produces a variety growth factors and cytokines that affect leukemia cells. Two such factors increase during treatment and appear to play a role in early resistance to FLT3 inhibitors such as gilteritinib. The researchers grew AML cells with the growth factors added to the mix, which created a model that recapitulated the unique features of early resistance seen in people with AML. The early resistant leukemia cells grew more slowly than typical leukemia cells, and they began to reprogram their metabolism to survive.

Experiments showed that early resistant cells became transiently sensitive to gilteritinib, the targeted therapy drug, when grown without supportive factors that are available to them in the bone marrow environment. But removing the supportive factors also led to the rise of many mutations in a gene called NRAS, mutations that make leukemia cells highly resistant to gilteritinib and other drugs that target FLT3, known as FLT3 inhibitors.

“We show that protective factors secreted by the AML bone marrow microenvironment are essential in fostering the development of early drug resistance, which precedes the acquisition of genetic mutations found at later stages of resistance,” Joshi said.

While NRAS mutations were detectable at low levels in early resistant cells, the mutations did not give the leukemia cells a growth advantage in the presence of survival factors from the marrow environment. Instead of relying on NRAS signaling, the early resistant cells required an enzyme called aurora kinase B (AURKB) for growth.

With this understanding, the researchers then tested a drug combination strategy: gilteritinib plus an inhibitor of AURKB to target early resistant AML cells before they have a chance to expand resistance mutations. They showed that early resistant cell cultures – and early resistant AML cells taken directly from patients – were all exquisitely sensitive to the combination.

“This strategy appears to be more attractive than combination therapies targeting mutations featured in late resistance, as alternate mutations might develop either as a consequence to or independent of the therapy,” Philippe Gui and Trever Bivona wrote in a commentary on the research. “This concept should be clinically tested and holds promise for improving outcomes in AML patients,” they said. “Overall, the work by Joshi et al. should prompt similar studies in other tumor types to augment the understanding of tumor evolution and drug resistance.”

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Further reading:

The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance
Sunil K. Joshi, Tamilla Nechiporuk, Daniel Bottomly, Karin D. Rodland, Brian J. Druker, Elie Traer and others. Cancer Cell (June 24, 2021)

Stepwise evolution of therapy resistance in AML by Philippe Gui and Trever G. Bivona. Cancer Cell (June 24, 2021)