Resistance to PI3K inhibitors in chronic lymphocytic leukemia (CLL) can be overcome by adding a MEK1/2 inhibitor to treatment, according to preclinical findings published in Blood.
To better understand resistance to PI3K inhibitors, researchers used whole-exome sequencing to analyze matched tumor and germline samples from 28 patients with CLL who received PI3K inhibitors.
Each patient had a median of 2 longitudinal tumor samples (range, 1-6) that were sequenced, yielding a total of 68 samples.
Based on their initial response to a PI3K inhibitor, patients were grouped as responders (n = 18) and nonresponders (n = 10). Samples were also grouped as responders (n = 47) and nonresponders (n = 21).
Analyses suggested that MAPK/ERK pathway activation mediates resistance to PI3K inhibitors. Six of the 10 nonresponders (60%) had MAPK pathway mutations — in KRAS, BRAF, and MAP2K1. On the other hand, only 1 of 18 (5.5%) responders had a MAPK pathway mutation — in NRAS (P <.005).
When wild-type CLL cells and CLL cells mutated to increase baseline ERK phosphorylation were exposed to a MEK1/2 inhibitor or an ERK1/2 inhibitor, there was a significant decline in ERK phosphorylation levels. There was no significant decline when the cells were exposed to the PI3K inhibitor idelalisib.
The researchers also compared survival of mutated and wild-type CLL cells after treatment with idelalisib. The mutated CLL cells lived longer, which indicates resistance to the PI3K inhibitor.
The combination of a MEK1/2 inhibitor with idelalisib blocked cell proliferation for both wild-type and mutated cells from 2 different CLL cell lines, suggesting that PI3K resistance was overcome.
“Treatment with MEK1/2 inhibitors, either alone or in combination with idelalisib, rescued this PI3K resistance in both primary leukemia cells and engineered cell lines, suggesting that the addition of [a] MEK inhibitor either at therapy start or as an add-in therapy during early progression may overcome PI3K inhibitor resistance,” the researchers concluded.
Disclosure: This research was funded, in part, by Gilead Sciences. Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Murali I, Kasar S, Naeem A, et al. Activation of the MAPK pathway mediates resistance to PI3K inhibitors in chronic lymphocytic leukemia (cll). Blood. Published online March 8, 2021. doi:10.1182/blood.2020006765