Dynamic Duo of Leukemia

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Erlotinib and ethacridine team up to stop cancer cell growth.
Posted On: November 29, 2016
By Shaalee Dworski, ORT Writer and UHN Trainee
Batman and Robin, Sherlock and Watson – great crime-fighters work better in pairs, and so do cancer-fighters. A great partnership between chemotherapy drugs often results in better patient outcomes.
Acute myeloid leukemia (AML) is a blood cancer that could benefit from a combination of chemotherapeutics. AML cells accumulate in the bone marrow as they over-proliferate, crowding out normal cells. Erlotinib is an effective drug against AML cells in vitro because it causes the cancer cells to undergo apoptosis, to stop proliferating or to differentiate. However, it hasn’t been as successful in clinical trials.
Lianne Rotin, a PhD student in Dr. Aaron Schimmer’s laboratory, and colleagues were looking for a drug that would complement erlotinib and lead to better cancer cell killing. They paired erlotinib with 1,352 other compounds from several chemical libraries and tested their ability to kill AML cell lines together.
Ethacridine was the compound that best paired with erlotinib. The combination of erlotinib and ethacridine resulted in an enhanced ability to kill AML cell lines and primary AML cells in vitro. Importantly, this combination did not enhance the killing of healthy blood cells. The erlotinib-ethacridine combination was also potent in vivo: the drugs reduced tumour growth in immune-compromised mice injected with AML cells.
Why are these two drugs so much better together? The authors propose that erlotinib may prevent transporter proteins in the cancer cells from effluxing ethacridine, leading to an accumulation of ethacridine within cells. More ethacridine in AML cells results in a greater increase in the production of reactive oxygen species (ROS), which leads to faster cell death.
Further preclinical and clinical studies will determine whether erlotinib and ethacridine are the one-two punch that AML never saw coming.

The ORT spoke with first author Lianne.


1.    Why did you choose erlotinib as the primary partner to treat AML?
Erlotinib has demonstrated good preclinical activity against several cellular targets that are important for AML cell proliferation and survival. Our goal was to "boost" this anti-leukemic activity by identifying drugs that synergized with erlotinib. Erlotinib is already used clinically to treat other types of cancer, so we know that it is safe and generally well-tolerated by patients. This means that erlotinib could be rapidly advanced to the AML clinic; a process that would be much faster than  developing of a brand new drug.

2.    Has the combination of erlotinib and ethacridine, a PARG inhibitor, been successful in other types of cancer?
To our knowledge this combination has never been studied in other cancers. A better understanding of the effects of PARG inhibition in AML and whether these effects extend to other cancer cell types are important areas for future study.

3.    Who is your favourite crime-fighting duo?
Scooby Doo & Shaggy!
Read the article here: https://www.ncbi.nlm.nih.gov/pubmed/2758738
Lianne Rotin, first author and UHN Trainee