Combined MEK-BRAF inhibition is a well-established treatment strategy in BRAF-mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF-MEK inhibitor treatment are unavailable. Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high-risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient.

CIC mutation as a molecular mechanism of acquired resistance to combined braf-mek inhibition in extramedullary multiple myeloma with central nervous system involvement / M.C. Da Via, A.G. Solimando, A. Garitano-Trojaola, S. Barrio, U. Munawar, S. Strifler, L. Haertle, N. Rhodes, E. Teufel, C. Vogt, C. Lapa, A. Beilhack, L. Rasche, H. Einsele, K.M. Kortum. - In: THE ONCOLOGIST. - ISSN 1083-7159. - 25:2(2020), pp. 112-118. [10.1634/theoncologist.2019-0356]

CIC mutation as a molecular mechanism of acquired resistance to combined braf-mek inhibition in extramedullary multiple myeloma with central nervous system involvement

M.C. Da Via
Primo
;
2020

Abstract

Combined MEK-BRAF inhibition is a well-established treatment strategy in BRAF-mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF-MEK inhibitor treatment are unavailable. Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high-risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient.
BRAF mutation; Capicua transcriptional repressor; Drug resistance; Extramedullary disease; Multiple myeloma
Settore MED/15 - Malattie del Sangue
2020
Article (author)
File in questo prodotto:
File Dimensione Formato  
oncolo_25_2_112.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 2.61 MB
Formato Adobe PDF
2.61 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/950761
Citazioni
  • ???jsp.display-item.citation.pmc??? 27
  • Scopus 40
  • ???jsp.display-item.citation.isi??? 39
social impact