Targeting CCL2/CCR2 Signaling Overcomes MEK Inhibitor Resistance in Acute Myeloid Leukemia
Issued Date
2024-05-15
Resource Type
eISSN
15573265
Scopus ID
2-s2.0-85193308905
Pubmed ID
38451486
Journal Title
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
30
Issue
10
Start Page
2245
End Page
2259
Rights Holder(s)
SCOPUS
Bibliographic Citation
Clinical cancer research : an official journal of the American Association for Cancer Research Vol.30 No.10 (2024) , 2245-2259
Suggested Citation
Modak R.V., de Oliveira Rebola K.G., McClatchy J., Mohammadhosseini M., Damnernsawad A., Kurtz S.E., Eide C.A., Wu G., Laderas T., Nechiporuk T., Gritsenko M.A., Hansen J.R., Hutchinson C., Gosline S.J.C., Piehowski P., Bottomly D., Short N., Rodland K., McWeeney S.K., Tyner J.W., Agarwal A. Targeting CCL2/CCR2 Signaling Overcomes MEK Inhibitor Resistance in Acute Myeloid Leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research Vol.30 No.10 (2024) , 2245-2259. 2259. doi:10.1158/1078-0432.CCR-23-2654 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/98460
Title
Targeting CCL2/CCR2 Signaling Overcomes MEK Inhibitor Resistance in Acute Myeloid Leukemia
Corresponding Author(s)
Other Contributor(s)
Abstract
PURPOSE: Emerging evidence underscores the critical role of extrinsic factors within the microenvironment in protecting leukemia cells from therapeutic interventions, driving disease progression, and promoting drug resistance in acute myeloid leukemia (AML). This finding emphasizes the need for the identification of targeted therapies that inhibit intrinsic and extrinsic signaling to overcome drug resistance in AML. EXPERIMENTAL DESIGN: We performed a comprehensive analysis utilizing a cohort of ∼300 AML patient samples. This analysis encompassed the evaluation of secreted cytokines/growth factors, gene expression, and ex vivo drug sensitivity to small molecules. Our investigation pinpointed a notable association between elevated levels of CCL2 and diminished sensitivity to the MEK inhibitors (MEKi). We validated this association through loss-of-function and pharmacologic inhibition studies. Further, we deployed global phosphoproteomics and CRISPR/Cas9 screening to identify the mechanism of CCR2-mediated MEKi resistance in AML. RESULTS: Our multifaceted analysis unveiled that CCL2 activates multiple prosurvival pathways, including MAPK and cell-cycle regulation in MEKi-resistant cells. Employing combination strategies to simultaneously target these pathways heightened growth inhibition in AML cells. Both genetic and pharmacologic inhibition of CCR2 sensitized AML cells to trametinib, suppressing proliferation while enhancing apoptosis. These findings underscore a new role for CCL2 in MEKi resistance, offering combination therapies as an avenue to circumvent this resistance. CONCLUSIONS: Our study demonstrates a compelling rationale for translating CCL2/CCR2 axis inhibitors in combination with MEK pathway-targeting therapies, as a potent strategy for combating drug resistance in AML. This approach has the potential to enhance the efficacy of treatments to improve AML patient outcomes.