CIC Mutation as a Molecular Mechanism of Acquired Resistance to Combined BRAF-MEK Inhibition in Extramedullary Multiple Myeloma with Central Nervous System Involvement

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. The Oncologist 2020;25:112-118 KEY POINTS• BRAF mutations constitute an attractive druggable target in multiple myeloma. This is the first genomic dissection of the central nervous system involvement in a multiple myeloma patient harboring a druggable BRAF V600E mutation. Deep genomic characterization of the extramedullary lesion prompted a personalized therapeutic approach. • Acquisition of CIC mutation confers a mechanism of BRAF-MEK inhibitor drug resistance in multiple myeloma.• The in silico interrogation of the CoMMpass clinical study revealed 10 patients with somatic mutations of CIC and its downregulation at gene expression level in multiple myeloma. • CIC gene silencing decreases the sensitivity of multiple myeloma cells to BRAF-MEK inhibition in vitro. The correlation between CIC downregulation and ETV4/5 nuclear factor expression in multiple myeloma BRAF-mutant cells is shown for the first time. • CIC mutation, its downregulation, and the related downstream effect on MMP24 support disseminative potential providing new clues in the extramedullary biology definition. PATIENT HISTORYAn 81-year-old patient with κ light chain multiple myeloma (MM) was referred to our center after having a seizure and increasing M-proteins. MM had been diagnosed 2 years before and the patient had undergone nine cycles of bortezomibbased combination therapy (VMP) resulting in an initial good disease control. Magnetic resonance imaging of the brain and Correspondence: K.

Phenotypic Variability of an Inherited Pathogenic Variant in CIC Gene: A New Case Report in Two-Generation Family and Literature Review

“…Studies have supported that these mutations are driver instead of passenger for these cells. 9,16,17 However, the conditional inactivating CIC selectively in postmitotic excitatory neurons in mouse brain using NEX-Cre results in a reduction in the number of cells expressing CUX1 and SATB2 in layer 2 of the cortex. 4 In contrast, using hematopoietic-specific deletion and bone marrow transplantation studies, the loss of Cic from hematopoietic cells results in upregulation of KRAS pathway and is sufficient to drive T cell acute lymphoblastic leukemia/lymphoma (T-ALL).…”

“…10,15 A large number of somatic variants have also been found in other non-CNS-related cancers such as lung cancer, gastric cancer, acute lymphocytic leukemia; these are not cataloged here. 6,16,17 The search of variant of CIC in gnomAD in February of 2020 has uncovered 12 loss of function variants that include seven splicing, two frameshift, and three stop-gain variants (►Supplementary Fig. S1).…”

HB-EGF–EGFR Signaling in Bone Marrow Endothelial Cells Mediates Angiogenesis Associated with Multiple Myeloma

“…It is also interesting to note that the mutational state of EGFR and the activation of the EGFR/Ras/ERK pathway associates with the central nervous system (CNS) tropism of several tumors [34][35][36][37] and that hyperstimulation of several tyrosine kinases and mitogen-activated protein kinases have been found in MM patients with aggressive disease and CNS involvement [38,39]. These patients that are usually p53 and/or BRAF mutated [40,41] show clinical response to pomalidomide [42] and could benefit from a combination of pomalidomide (or other IMiDs) and EGFR-targeted agents, such as cetuximab [43].…”

Role of BRAF in Hepatocellular Carcinoma: A Rationale for Future Targeted Cancer Therapies

“…We need of specific diagnostic tests to predict HCC response to BRAF-MEK inhibitors. Nonetheless, novel insights suggested significant investigation in solid and hematological malignancies, with initial with promising results [42,43]. Recently, several data confirmed that different doses of TKIs determine inhibition or iper-activaction of the MAPK pathway, with opposite effects.…”