PTEN deletion drives acute myeloid leukemia resistance to MEK inhibitors


To identify possible causes of resistance to MEK inhibition, this research team generated a model of resistance by long-term treatment of AML cells with AZD6244.

Remarkably, resistance to MEK inhibition was due to acquired PTEN haploinsufficiency, rather than mutation of MEK.

Dr. Andrew S. Moore from the University of Queensland Diamantina Institute and the Child Health Research Centre at the University of Queensland in Woolloongabba, Australia as well as the Oncology Services Group at Queensland Children's Hospital in South Brisbane, Australia and finally the Washington University in Saint Louis, Saint Louis, Missouri, United States of America & Dr. J. Lynn Fink, also from the University of Queensland Diamantina Institute at The University of Queensland in Woolloongabba, Australia said, "Pediatric acute myeloid leukemia (AML) causes a disproportionate number of childhood cancer deaths [1, 2]. The peak incidence of childhood AML occurs in children under 4 years (1.1 per 100,000; 1982–2007)"

Figure 1: Copy number changes acquired during generation of MEKi-resistant phenotype.

Figure 1: Copy number changes acquired during generation of MEKi-resistant phenotype. Copy number variation analysis of all TR populations revealed amplification and deletion events common to all samples which are known to be associated with cancer and/or drug resistance. These events include deletion of PTEN, IRF4, and ELOLV2 and amplification of KRAS. TR copy changes are shown relative to DMSO controls. Each panel describes copy changes for the chromosome indicated in the title bar. Circle size indicates the statistical significance of the difference in gene copies (Bonferroni-adjusted p-values); large circles represent p < 0.001, medium circles represent 0.001 < p < 0.05; and small circles represent p ≥ 0.05. Circle colour represents replicates.

However, the frequent development of resistance to kinase inhibitors, such as imatinib and sorafenib, through a variety of mechanisms such as acquisition of additional mutations within the kinase domains of the target proteins, leads the scientists to an important question: will MEK inhibitor utility in AML be limited by rapid selection and expansion of subclones that either express or develop intrinsically resistant mutations in the pathway or that lack dependence on MEK signaling for growth and survival?

To answer this question, they established an in vitro model of MEK inhibitor resistance using THP-1 cells, incubated in increasing concentrations of selumetinib, to identify the mechanism that may lead to resistance in AML patients.

We also confirmed that disruption of the PTEN catalytic core motif domain was the mechanism of resistance using CRISPR-mediated deletion of PTEN exon 5, a region which contributes to the catalytic activity of this tumour suppressor .

Given the observation that PTEN deletion is a mechanism for MEKi resistance in solid tumours, and that deletion of PTEN in AML is sufficient to confer resistance, we propose that this event can be used as a biomarker of MEK inhibitor resistance in AML. This is also the first report of PTEN deletion as a mechanism of small molecule inhibitor resistance in AML.

The Moore/Fink Research Team concluded, "We were also able to demonstrate that MEKi synergize with other chemotherapeutic compounds, at least in some cases, so, while MEKi utility in AML is clearly limited by the development of resistant subclones, combination therapy may be a viable strategy to mitigate this effect."

Full text - https://doi.org/10.18632/oncotarget.27206

Correspondence to - Andrew S. Moore - [email protected] and J. Lynn Fink - [email protected]

Keywords - myeloid leukemia, therapy, drug resistance, hematological malignancies, gene mutation

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