Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma

被引：4

作者：

Krebs, Fanny Seraphine ^{[1
,2
]}

Moura, Bianca ^{[3
]}

Missiaglia, Edoardo ^{[4
,5
]}

Aedo-Lopez, Veronica ^{[6
]}

Michielin, Olivier ^{[5
,7
,8
,9
,10
]}

Tsantoulis, Petros ^{[9
,10
]}

Bisig, Bettina ^{[4
]}

Trimech, Mounir ^{[4
]}

Zoete, Vincent ^{[1
,2
,5
,9
]}

Homicsko, Krisztian ^{[2
,7
,8
,9
]}

机构：

[1] Univ Lausanne, Dept Oncol UNIL CHUV, Comp Aided Mol Engn, CH-1015 Lausanne, Switzerland

[2] Ludwig Inst Canc Res, CH-1005 Lausanne, Switzerland

[3] Serv Med Oncol, CH-1700 Fribourg, Switzerland

[4] Lausanne Univ, Inst Pathol, Ctr Hosp Univ Vaudois, Dept Lab Med & Pathol, CH-1011 Lausanne, Switzerland

[5] SIB Swiss Inst Bioinformat, Mol Modelling Grp, CH-1015 Lausanne, Switzerland

[6] Monash Med Ctr, Clayton, Vic 3168, Australia

[7] CHU Vaudois, Dept Oncol, Serv Med Oncol, CH-1011 Lausanne, Switzerland

[8] CHU Vaudois, Ctr Personalized Oncol, Dept Oncol, CH-1011 Lausanne, Switzerland

[9] Swiss Canc Ctr Leman, CH-1005 Lausanne, Switzerland

[10] Hop Univ Geneve, Dept Oncol, CH-1205 Geneva, Switzerland

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2023年 / 24卷 / 05期

关键词：

cancer; triple-negative melanoma; modelling; mutation; PROTEIN; MUTATIONS; MEK; INHIBITION; LANDSCAPE; COMPLEXES; MAP2K1; BRAF;

D O I：

10.3390/ijms24054520

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The development of targeted therapies for non-BRAF p.Val600-mutant melanomas remains a challenge. Triple wildtype (TWT) melanomas that lack mutations in BRAF, NRAS, or NF1 form 10% of human melanomas and are heterogeneous in their genomic drivers. MAP2K1 mutations are enriched in BRAF-mutant melanoma and function as an innate or adaptive resistance mechanism to BRAF inhibition. Here we report the case of a patient with TWT melanoma with a bona fide MAP2K1 mutation without any BRAF mutations. We performed a structural analysis to validate that the MEK inhibitor trametinib could block this mutation. Although the patient initially responded to trametinib, he eventually progressed. The presence of a CDKN2A deletion prompted us to combine a CDK4/6 inhibitor, palbociclib, with trametinib but without clinical benefit. Genomic analysis at progression showed multiple novel copy number alterations. Our case illustrates the challenges of combining MEK1 and CDK4/6 inhibitors in case of resistance to MEK inhibitor monotherapy.

引用

页数：12

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