Researchers identified a possible role for activating mutations in MAPK pathway genes in the development of resistance to phosphatidylinositol 3-kinase (PI3K) inhibitors in treatment of chronic lymphocytic leukemia (CLL). Results were reported in the journal Blood.

The findings came from a study of longitudinal whole-exome sequencing (WES) of cells in patients with CLL, most of whom had experienced multiple relapses. Patients had been participants of clinical trials evaluating the use of PI3K inhibitors. WES was performed on both tumor and germline cells, and key somatic mutations and clonality estimations were determined based on algorithms generated by the Broad Institute’s Cancer Genome Analysis Group. Patients were divided according to response status with initial PI3K inhibitor treatment.

This analysis included a total of 28 patients with relapsed CLL who received treatment with PI3K inhibitors. The median number of prior treatments was 4.5 (range, 0-6), and there was a median of 7.9 years (range, 0.1-19.2) that passed between diagnosis and sampling in this study. The median time from diagnosis to first treatment in the overall population was 2.0 years (range, 0-7.4). Patients had a median of 2 longitudinal tumor samples (range, 1-6) that were sequenced, with a total of 68 samples evaluated.

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The majority of patients (78.57%) had received the PI3Kd inhibitor idelalisib, while pilaralisib and voxtalisib were each given to approximately 11% of patients. Patients showed del(17p) status at a rate of 18%, and del(11q) status at a rate of 32%. A total of 18 of the patients, with 47 samples, were responders to initial PI3K inhibitor therapy, while 10 patients, with 21 samples, were classified as nonresponders.

Genes that were found to be mutated exclusively in some nonresponders in this study were included BRAF, KRAS, MAP2K1, XPO1, PLEKHA1, NXF1, and INPPL1 genes. Mutations in MAPK pathway genes, which included KRAS, BRAF, and MAP2K1, were seen among 60% of nonresponders.

A phenomenon observed in CLL cells from patients who were nonresponders was that PI3Kd inhibition demonstrated an inability to inhibit ERK phosphorylation. Additionally, patients with MAP2K1 mutations showed higher levels of ERK phosphorylation when MAP2K1 was overexpressed, and idelalisib resistance appeared increased in this circumstance.

The study investigators concluded that PI3Kd inhibitor resistance in CLL may be linked to activation of MAPK and ERK pathways. “In summary, our findings provide evidence that MAPK pathway mutations drive primary resistance to PI3K inhibitors in CLL,” they wrote in their report. They continued, “[w]e identified MAP2K1 (20%) and MAPK pathway mutations (60%) as being enriched among patients for whom treatment with PI3K inhibitors failed.”

Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Murali I, Kasar S, Naeem A, et al. Activation of the MAPK pathway mediates resistance to PI3K inhibitors in chronic lymphocytic leukemia. Blood. 2021;138(1):44-56. doi:10.1182/blood.2020006765