by ecancer reporter Janet Fricker

A mechanism for acute myeloid leukaemia (AML) drug resistance has been uncovered in a Canadian study, reports a letter in Nature.

Responses of AML patients to cytarabine (Ara-C) based therapies are often short lived with median overalls survival of months.

At first a phase II clinical trial of poor prognosis AML patients with ribavirin mono therapy, published in Blood in 2009, yielded promising responses (including remissions), but eventually all patients relapsed.

In the current study Katherine Borden and colleagues, from the University of Montreal, Canada, observed that the sonic hedgehog transcription factor glioma-associated protein 1 (GLI1) and the UDP glucuronosyltransferase (UGT1A) family of enzymes were elevated in resistant cells.

UGT1As are known to add glucuronic acid to many drugs, thereby modifying their activity.

The investigators showed GLI1 mRNA levels were substantially elevated at relapse relative to diagnosis in seven out of nine patients failing more commonly used Ara-C therapies.

Next, they showed that GLI1 alone was sufficient to drive UGT1A-dependent glucuronidation of ribavirin and Ara-C, and thus drug resistance.

Growth of AML cells that over express GLI1 AML cells were not substantially affected by levels of ribavirin or Ara-C that impaired growth of normal AML cells.

Furthermore, GLI1 knockdown re-sensitized FRII cells to ribavirin and Ara-C.

Finally, investigators showed when AML cells were pre-treated with a clinically approved inhibitor of sonic hedgehog signalling followed by Ara-C, a 60% reduction in growth was achieved relatively to untreated cells.

“Our findings reveal a role for GLI1 in drug metabolism and resistance. Here, GLI1 inhibition could restore drug sensitivity and thereby provide therapeutic benefit,” write the authors. Reference H Ahmad Zahreddine, B Culjkovic-Kraljacic, S Assouline, et al.

The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation.

Reference

H Ahmad Zahreddine, B Culjkovic-Kraljacic, S Assouline, et al. The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation. Nature.