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Volume 26
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10.3390/ijms262311448
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Targeting the MEK/ERK Pathway to Suppress P-Glycoprotein and Reverse Carfilzomib Resistance in Multiple Myeloma

by
Lidia A. Laletina
1,
Anastasiia I. Cherkasova
1,
Ekaterina A. Scherbakova
1,
Pavel S. Iamshchikov
2,
Natalia A. Koroleva
1,
Anna A. Lushnikova
1,
Alexey A. Komissarov
3,4,
Nikolay Kalitin
1 and
Natalia I. Moiseeva
1,*
1
N.N. Blokhin National Medical Research Center of Oncology, Kashirskoe Shosse 24, 115478 Moscow, Russia
2
Center for Systems Bioinformatics, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050 Tomsk, Russia
3
I.V. Davydovsky Moscow City Clinical Hospital, Moscow Department of Healthcare, 117463 Moscow, Russia
4
Laboratory of Atherothrombosis, The Russian University of Medicine, 127473 Moscow, Russia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(23), 11448; https://doi.org/10.3390/ijms262311448 (registering DOI)
Submission received: 30 October 2025 / Revised: 20 November 2025 / Accepted: 23 November 2025 / Published: 26 November 2025
(This article belongs to the Special Issue Research in Membrane Transporters—Unveiling the Molecular Mechanisms and Practical Application)
Review Reports Versions Notes

Abstract

Carfilzomib (CFZ) is a cornerstone in the treatment of relapsed multiple myeloma (MM). However, its efficacy is limited by resistance mediated by the overexpression of the ABC-transporter P-glycoprotein (P-gp). The signaling pathways driving the emergence of P-gp in MM remain unclear. To investigate this, we generated CFZ-resistant AMO-1/CFZ cells with P-gp overexpression by long-term selection. RNA sequencing of control AMO-1 and AMO-1/CFZ, sorted into two subpopulations, P-gp HIGH and P-gp LOW, implicated the Ras/MEK/ERK pathway as the most likely signaling cascade involved in P-gp upregulation. We therefore evaluated two clinically used MAPK pathway inhibitors, cobimetinib and ulixertinib, for their ability to re-sensitize AMO-1/CFZ cells to CFZ. Co-administration at non-toxic concentrations enhanced sensitivity 5-fold with cobimetinib and 17-fold with ulixertinib. Analysis of the combined MTT assay results, rhodamine efflux experiments, molecular docking, and Western blotting revealed distinct actions. Ulixertinib primarily functions as a potent direct P-gp inhibitor. Conversely, non-toxic concentrations of cobimetinib sensitizes cells by suppressing MAPK signaling, though it also exhibits P-gp inhibition at higher concentrations. At the IC50 concentration, both inhibitors reduced P-gp expression. In conclusion, combining CFZ with MAPK pathway inhibitors like cobimetinib or ulixertinib represents a promising strategy to overcome P-gp-mediated resistance in MM.
Keywords: P-glycoprotein; carfilzomib; multiple myeloma; ulixertinib; cobimetinib; MAPK pathway; MEK inhibitors; ERK inhibitors; RNAseq P-glycoprotein; carfilzomib; multiple myeloma; ulixertinib; cobimetinib; MAPK pathway; MEK inhibitors; ERK inhibitors; RNAseq

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MDPI and ACS Style

Laletina, L.A.; Cherkasova, A.I.; Scherbakova, E.A.; Iamshchikov, P.S.; Koroleva, N.A.; Lushnikova, A.A.; Komissarov, A.A.; Kalitin, N.; Moiseeva, N.I. Targeting the MEK/ERK Pathway to Suppress P-Glycoprotein and Reverse Carfilzomib Resistance in Multiple Myeloma. Int. J. Mol. Sci. 2025, 26, 11448. https://doi.org/10.3390/ijms262311448

AMA Style

Laletina LA, Cherkasova AI, Scherbakova EA, Iamshchikov PS, Koroleva NA, Lushnikova AA, Komissarov AA, Kalitin N, Moiseeva NI. Targeting the MEK/ERK Pathway to Suppress P-Glycoprotein and Reverse Carfilzomib Resistance in Multiple Myeloma. International Journal of Molecular Sciences. 2025; 26(23):11448. https://doi.org/10.3390/ijms262311448

Chicago/Turabian Style

Laletina, Lidia A., Anastasiia I. Cherkasova, Ekaterina A. Scherbakova, Pavel S. Iamshchikov, Natalia A. Koroleva, Anna A. Lushnikova, Alexey A. Komissarov, Nikolay Kalitin, and Natalia I. Moiseeva. 2025. "Targeting the MEK/ERK Pathway to Suppress P-Glycoprotein and Reverse Carfilzomib Resistance in Multiple Myeloma" International Journal of Molecular Sciences 26, no. 23: 11448. https://doi.org/10.3390/ijms262311448

APA Style

Laletina, L. A., Cherkasova, A. I., Scherbakova, E. A., Iamshchikov, P. S., Koroleva, N. A., Lushnikova, A. A., Komissarov, A. A., Kalitin, N., & Moiseeva, N. I. (2025). Targeting the MEK/ERK Pathway to Suppress P-Glycoprotein and Reverse Carfilzomib Resistance in Multiple Myeloma. International Journal of Molecular Sciences, 26(23), 11448. https://doi.org/10.3390/ijms262311448

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