Targeting CCL2/CCR2 Signaling Overcomes MEK Inhibitor Resistance in Acute Myeloid Leukemia

Modak, Rucha V.; de Oliveira Rebola, Katia G.; McClatchy, John; Mohammadhosseini, Mona; Damnernsawad, Alisa; Kurtz, Stephen E.; Eide, Christopher A.; Wu, Guanming; Laderas, Ted; Nechiporuk, Tamilla; Gritsenko, Marina A.; Hansen, Joshua R.; Hutchinson, Chelsea M.; Gosline, Sara J. C.; Piehowski, Paul; Bottomly, Daniel; Short, Nicholas; Rodland, Karin; McWeeney, Shannon K.; Tyner, Jeffrey W.; Agarwal, Anupriya

doi:10.1158/1078-0432.ccr-23-2654

Title: Targeting CCL2/CCR2 Signaling Overcomes MEK Inhibitor Resistance in Acute Myeloid Leukemia

Journal Article · 06 March 2024 · Clinical Cancer Research

DOI: https://doi.org/10.1158/1078-0432.ccr-23-2654 · OSTI ID:2448371

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Oregon Health & Science Univ., Portland, OR (United States)
Oregon Health & Science Univ., Portland, OR (United States); Mahidol University, Bangkok (Thailand)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States); Oregon Health & Science Univ., Portland, OR (United States)
MD Anderson Cancer Center, Houston, TX (United States)

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. 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. 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. 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.

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Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2448371

Report Number(s):: PNNL-SA--187155

Journal Information:: Clinical Cancer Research, Journal Name: Clinical Cancer Research Journal Issue: 10 Vol. 30; ISSN 1078-0432

Publisher:: American Association for Cancer ResearchCopyright Statement

Country of Publication:: United States

Language:: English

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Title: Targeting CCL2/CCR2 Signaling Overcomes MEK Inhibitor Resistance in Acute Myeloid Leukemia

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