TY - JOUR A1 - Ruiz-Heredia, Yanira A1 - Sánchez-Vega, Beatriz A1 - Onecha, Esther A1 - Barrio, Santiago A1 - Alonso, Rafael A1 - Carlos Martínez-Avila, Jose A1 - Cuenca, Isabel A1 - Agirre, Xabier A1 - Braggio, Esteban A1 - Hernández, Miguel-T. A1 - Martínez, Rafael A1 - Rosiñol, Laura A1 - Gutierrez, Norma A1 - Martin-Ramos, Marisa A1 - Ocio, Enrique M. A1 - Echeveste, María-Asunción A1 - Pérez de Oteyza, Jaime A1 - Oriol, Albert A1 - Bargay, Joan A1 - Gironella, Mercedes A1 - Ayala, Rosa A1 - Bladé, Joan A1 - Mateos, María-Victoria A1 - Kortum, Klaus M. A1 - Stewart, Keith A1 - García-Sanz, Ramón A1 - San Miguel, Jesús A1 - José Lahuerta, Juan A1 - Martinez-Lopez, Joaquín T1 - Mutational screening of newly diagnosed multiple myeloma patients by deep targeted sequencing JF - Haematologica N2 - no abstract available KW - Copy number changes KW - Survival Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227151 VL - 103 IS - 11 ER - TY - JOUR A1 - Haertle, Larissa A1 - Buenache, Natalia A1 - Cuesta Hernández, Hipólito Nicolás A1 - Simicek, Michal A1 - Snaurova, Renata A1 - Rapado, Inmaculada A1 - Martinez, Nerea A1 - López-Muñoz, Nieves A1 - Sánchez-Pina, José María A1 - Munawar, Umair A1 - Han, Seungbin A1 - Ruiz-Heredia, Yanira A1 - Colmenares, Rafael A1 - Gallardo, Miguel A1 - Sanchez-Beato, Margarita A1 - Piris, Miguel Angel A1 - Samur, Mehmet Kemal A1 - Munshi, Nikhil C. A1 - Ayala, Rosa A1 - Kortüm, Klaus Martin A1 - Barrio, Santiago A1 - Martínez-López, Joaquín T1 - Genetic alterations in members of the proteasome 26S subunit, AAA-ATPase (PSMC) gene family in the light of proteasome inhibitor resistance in multiple myeloma JF - Cancers N2 - For the treatment of Multiple Myeloma, proteasome inhibitors are highly efficient and widely used, but resistance is a major obstacle to successful therapy. Several underlying mechanisms have been proposed but were only reported for a minority of resistant patients. The proteasome is a large and complex machinery. Here, we focus on the AAA ATPases of the 19S proteasome regulator (PSMC1-6) and their implication in PI resistance. As an example of cancer evolution and the acquisition of resistance, we conducted an in-depth analysis of an index patient by applying FISH, WES, and immunoglobulin-rearrangement sequencing in serial samples, starting from MGUS to newly diagnosed Multiple Myeloma to a PI-resistant relapse. The WES analysis uncovered an acquired PSMC2 Y429S mutation at the relapse after intensive bortezomib-containing therapy, which was functionally confirmed to mediate PI resistance. A meta-analysis comprising 1499 newly diagnosed and 447 progressed patients revealed a total of 36 SNVs over all six PSMC genes that were structurally accumulated in regulatory sites for activity such as the ADP/ATP binding pocket. Other alterations impact the interaction between different PSMC subunits or the intrinsic conformation of an individual subunit, consequently affecting the folding and function of the complex. Interestingly, several mutations were clustered in the central channel of the ATPase ring, where the unfolded substrates enter the 20S core. Our results indicate that PSMC SNVs play a role in PI resistance in MM. KW - Multiple Myeloma KW - drug resistance KW - proteasome inhibitors KW - immunoglobulin rearrangement KW - ATPase activity KW - PSMC2 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305013 SN - 2072-6694 VL - 15 IS - 2 ER - TY - JOUR A1 - Da Vià, Matteo Claudio A1 - Solimando, Antonio Giovanni A1 - Garitano-Trojaola, Andoni A1 - Barrio, Santiago A1 - Munawar, Umair A1 - Strifler, Susanne A1 - Haertle, Larissa A1 - Rhodes, Nadine A1 - Vogt, Cornelia A1 - Lapa, Constantin A1 - Beilhack, Andreas A1 - Rasche, Leo A1 - Einsele, Hermann A1 - Kortüm, K. Martin T1 - CIC Mutation as a Molecular Mechanism of Acquired Resistance to Combined BRAF‐MEK Inhibition in Extramedullary Multiple Myeloma with Central Nervous System Involvement JF - The Oncologist N2 - 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. KW - Multiple myeloma KW - Extramedullary disease KW - Capicua transcriptional repressor KW - Drug resistance KW - BRAF mutation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219549 VL - 25 IS - 2 ER -