Trametinib-Resistant Melanoma Cells Displaying MITF<sup>high</sup>/NGFR<sup>low</sup>/IL-8<sup>low</sup> Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge
Despite significant advances in targeted therapies against the hyperactivated BRAF<sup>V600</sup>/MEK pathway for patients with unresectable metastatic melanoma, acquired resistance remains an unsolved clinical problem. In this study, we focused on melanoma cells resistant to trametinib,...
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MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/9/7891 |
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| author | Paulina Koziej Katarzyna Kluszczynska Mariusz L. Hartman Malgorzata Czyz |
| author_facet | Paulina Koziej Katarzyna Kluszczynska Mariusz L. Hartman Malgorzata Czyz |
| author_sort | Paulina Koziej |
| collection | DOAJ |
| description | Despite significant advances in targeted therapies against the hyperactivated BRAF<sup>V600</sup>/MEK pathway for patients with unresectable metastatic melanoma, acquired resistance remains an unsolved clinical problem. In this study, we focused on melanoma cells resistant to trametinib, an agent broadly used in combination therapies. Molecular and cellular changes were assessed during alternating periods of trametinib withdrawal and rechallenge in trametinib-resistant cell lines displaying either a differentiation phenotype (MITF<sup>high</sup>/NGFR<sup>low</sup>) or neural crest stem-like dedifferentiation phenotype (NGFR<sup>high</sup>/MITF<sup>low</sup>). Neither drug withdrawal nor drug rechallenge induced cell death, and instead of loss of fitness, trametinib-resistant melanoma cells adapted to altered conditions by phenotype switching. In resistant cells displaying a differentiation phenotype, trametinib withdrawal markedly decreased MITF level and activity, which was associated with reduced cell proliferation capacity, and induced stemness assessed as NGFR-positive cells and senescence features, including IL-8 expression and secretion. All these changes could be reversed by trametinib re-exposure, which emphasizes melanoma cell plasticity. Trametinib-resistant cells displaying a dedifferentiation phenotype were less responsive presumably due to the already low level of MITF, a master regulator of the melanoma phenotype. Considering new directions of the development of anti-melanoma treatment, our study suggests that the phenotype of melanomas resistant to targeted therapy might be a crucial determinant of the selection of second-line therapy for melanoma patients. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:17:25Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b42a5f3619d54b16aef21cc4dc543c0e2023-11-17T23:02:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01249789110.3390/ijms24097891Trametinib-Resistant Melanoma Cells Displaying MITF<sup>high</sup>/NGFR<sup>low</sup>/IL-8<sup>low</sup> Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug RechallengePaulina Koziej0Katarzyna Kluszczynska1Mariusz L. Hartman2Malgorzata Czyz3Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215 Lodz, PolandDepartment of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215 Lodz, PolandDepartment of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215 Lodz, PolandDepartment of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215 Lodz, PolandDespite significant advances in targeted therapies against the hyperactivated BRAF<sup>V600</sup>/MEK pathway for patients with unresectable metastatic melanoma, acquired resistance remains an unsolved clinical problem. In this study, we focused on melanoma cells resistant to trametinib, an agent broadly used in combination therapies. Molecular and cellular changes were assessed during alternating periods of trametinib withdrawal and rechallenge in trametinib-resistant cell lines displaying either a differentiation phenotype (MITF<sup>high</sup>/NGFR<sup>low</sup>) or neural crest stem-like dedifferentiation phenotype (NGFR<sup>high</sup>/MITF<sup>low</sup>). Neither drug withdrawal nor drug rechallenge induced cell death, and instead of loss of fitness, trametinib-resistant melanoma cells adapted to altered conditions by phenotype switching. In resistant cells displaying a differentiation phenotype, trametinib withdrawal markedly decreased MITF level and activity, which was associated with reduced cell proliferation capacity, and induced stemness assessed as NGFR-positive cells and senescence features, including IL-8 expression and secretion. All these changes could be reversed by trametinib re-exposure, which emphasizes melanoma cell plasticity. Trametinib-resistant cells displaying a dedifferentiation phenotype were less responsive presumably due to the already low level of MITF, a master regulator of the melanoma phenotype. Considering new directions of the development of anti-melanoma treatment, our study suggests that the phenotype of melanomas resistant to targeted therapy might be a crucial determinant of the selection of second-line therapy for melanoma patients.https://www.mdpi.com/1422-0067/24/9/7891cancer cell plasticitydrug holidaydrug rechallengeIL-8MITFmelanoma |
| spellingShingle | Paulina Koziej Katarzyna Kluszczynska Mariusz L. Hartman Malgorzata Czyz Trametinib-Resistant Melanoma Cells Displaying MITF<sup>high</sup>/NGFR<sup>low</sup>/IL-8<sup>low</sup> Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge International Journal of Molecular Sciences cancer cell plasticity drug holiday drug rechallenge IL-8 MITF melanoma |
| title | Trametinib-Resistant Melanoma Cells Displaying MITF<sup>high</sup>/NGFR<sup>low</sup>/IL-8<sup>low</sup> Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge |
| title_full | Trametinib-Resistant Melanoma Cells Displaying MITF<sup>high</sup>/NGFR<sup>low</sup>/IL-8<sup>low</sup> Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge |
| title_fullStr | Trametinib-Resistant Melanoma Cells Displaying MITF<sup>high</sup>/NGFR<sup>low</sup>/IL-8<sup>low</sup> Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge |
| title_full_unstemmed | Trametinib-Resistant Melanoma Cells Displaying MITF<sup>high</sup>/NGFR<sup>low</sup>/IL-8<sup>low</sup> Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge |
| title_short | Trametinib-Resistant Melanoma Cells Displaying MITF<sup>high</sup>/NGFR<sup>low</sup>/IL-8<sup>low</sup> Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge |
| title_sort | trametinib resistant melanoma cells displaying mitf sup high sup ngfr sup low sup il 8 sup low sup phenotype are highly responsive to alternating periods of drug withdrawal and drug rechallenge |
| topic | cancer cell plasticity drug holiday drug rechallenge IL-8 MITF melanoma |
| url | https://www.mdpi.com/1422-0067/24/9/7891 |
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