{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:47:59Z","timestamp":1787838479345,"version":"build-2784847793"},"reference-count":69,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["24-25-00491"],"award-info":[{"award-number":["24-25-00491"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms262311448","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T14:39:43Z","timestamp":1764167983000},"page":"11448","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting the MEK\/ERK Pathway to Suppress P-Glycoprotein and Reverse Carfilzomib Resistance in Multiple Myeloma"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8839-5881","authenticated-orcid":false,"given":"Lidia A.","family":"Laletina","sequence":"first","affiliation":[{"name":"N.N. Blokhin National Medical Research Center of Oncology, Kashirskoe Shosse 24, 115478 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0236-2796","authenticated-orcid":false,"given":"Anastasiia I.","family":"Cherkasova","sequence":"additional","affiliation":[{"name":"N.N. Blokhin National Medical Research Center of Oncology, Kashirskoe Shosse 24, 115478 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5651-1454","authenticated-orcid":false,"given":"Ekaterina A.","family":"Scherbakova","sequence":"additional","affiliation":[{"name":"N.N. Blokhin National Medical Research Center of Oncology, Kashirskoe Shosse 24, 115478 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0646-6093","authenticated-orcid":false,"given":"Pavel S.","family":"Iamshchikov","sequence":"additional","affiliation":[{"name":"Center for Systems Bioinformatics, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050 Tomsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1663-4270","authenticated-orcid":false,"given":"Natalia A.","family":"Koroleva","sequence":"additional","affiliation":[{"name":"N.N. Blokhin National Medical Research Center of Oncology, Kashirskoe Shosse 24, 115478 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna A.","family":"Lushnikova","sequence":"additional","affiliation":[{"name":"N.N. Blokhin National Medical Research Center of Oncology, Kashirskoe Shosse 24, 115478 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1018-5195","authenticated-orcid":false,"given":"Alexey A.","family":"Komissarov","sequence":"additional","affiliation":[{"name":"I.V. Davydovsky Moscow City Clinical Hospital, Moscow Department of Healthcare, 117463 Moscow, Russia"},{"name":"Laboratory of Atherothrombosis, The Russian University of Medicine, 127473 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolay","family":"Kalitin","sequence":"additional","affiliation":[{"name":"N.N. Blokhin National Medical Research Center of Oncology, Kashirskoe Shosse 24, 115478 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6697-7154","authenticated-orcid":false,"given":"Natalia I.","family":"Moiseeva","sequence":"additional","affiliation":[{"name":"N.N. Blokhin National Medical Research Center of Oncology, Kashirskoe Shosse 24, 115478 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e70067","DOI":"10.1002\/hon.70067","article-title":"Multiple Myeloma Unpacked","volume":"43","author":"Gay","year":"2025","journal-title":"Hematol. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.annonc.2020.11.014","article-title":"Multiple Myeloma: EHA-ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up\u2020","volume":"32","author":"Dimopoulos","year":"2021","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. 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