and Charles Mullighan
Photo courtesy of St. Jude
Children’s Research Hospital
and Peter Barta
Retinoids and FAK inhibitors may override resistance to tyrosine kinase inhibitors (TKIs) in IKZF1-mutated, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), according to preclinical research published in Cancer Cell.
Experiments showed that, in Ph+ ALL, IKZF1 mutations prompt changes that reduce responsiveness to TKIs. But combining a TKI with a retinoid or FAK inhibitor can overcome this problem.
“The research shows why, in this era of targeted therapies, Ph+ ALL patients who also have IKZF1 mutations fare so poorly,” said study author Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee. “The insight also led us to a promising new treatment strategy.”
To conduct this research, Dr Mullighan and his colleagues began with mouse models of IKZF1-mutated Ph+ ALL, with and without mutations in the ARF gene. ARF encodes a tumor suppressor protein and is altered in about half of Ph+ ALL cases.
With these models, the researchers showed that the addition of IKZF1 mutations, particularly in combination with ARF mutations, was a central event in driving ALL.
In pre-B cells with BCR-ABL1, IKZF1 mutations induced a stem cell-like phenotype, increased stromal bone marrow adhesion, and reduced responsiveness to the TKI dasatinib.
When the researchers investigated the increased adhesion of mutated cells, they found overexpression of FAK and other molecules implicated in leukemic and stem cell adherence. This led the researchers to speculate that FAK inhibitors might prove useful against IKZF1-mutated Ph+ ALL.
But the team also found, through a screen of 483 compounds, that retinoids can reverse the effects of IKZF1 mutations. The antineoplastic agent bexarotene and 4 nuclear hormone receptor effectors—carbacyclin, all-trans retinoic acid (ATRA), 9-cis RA, and 13-cis RA—proved particularly effective.
The drugs worked, in part, by inducing expression of wild-type IKZF1. But they also worked in other ways to reverse the stem-cell phenotype, halt cell proliferation, and promote differentiation of altered cells.
The researchers then tested bexarotene and dasatinib, alone and in combination, in mice transplanted with ARF-/- BCR-ABL1 pre-B cells, with or without IK6 expression. Bexarotene alone produced “significant benefit without detectable toxicity.”
Dasatinib alone increased survival, but dasatinib and bexarotene in combination resulted in a greater survival advantage. The combination nearly doubled the survival time of mice with IK6 tumors, when compared to dasatinib alone.
The researchers also established xenografts of Ph+ ALL that recapitulate a range of IKZF1 genotypes. They administered dasatinib plus bexarotene, ATRA, or the FAK inhibitors PF-562271, NVPTAE226, or PF-573228 ex vivo and observed “significant potentiation of cell killing.”
The team is currently investigating how to incorporate retinoids or FAK inhibitors into the existing treatment of IKZF1-mutated Ph+ ALL.
