Determining resistance mechanisms in BRAF and RAS mutated multiple myeloma

• Applicant: Dr. Johannes Moritz Waldschmidt
• Subject Area: Hematology, Oncology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 391926441

Multiple myeloma (MM) is a B-cell lymphoid neoplasia which accounts for 10% of all hematologic malignancies. Despite improved treatment options, it remains an incurable disease as eventually all patients become refractory to current FDA-approved regimens. Clonal evolution and outgrowth of clones that harbor resistance mutations are likely patterns for the emergence of drug-resistant disease. Recent reports on the clonal landscape of MM have revealed activating mutations in BRAF and RAS kinase as potential therapeutic targets. BRAF mutations are present in ~5-12% of all patients, noting higher prevalence in refractory and extramedullary disease. These findings suggest a central role for the activation of the MAPK pathway in the biology of MM. To comprehensively assess resistance to BRAF/MEK inhibition as a novel treatment target in MM, the Dana-Farber Cancer Institute has recently initiated an IRB-approved phase I/II clinical trial. In this trial, patients with relapsed/refractory BRAF-mutated MM will be treated with either a BRAF inhibitor or a BRAF/MEK inhibitor combination while patients with NRAS/ KRAS mutations will undergo MEK inhibitor treatment. The here depicted project provides the translational genomic and biological assessment for this trial. By performing isolation and deep sequencing of cell-free DNA with matched bone marrow (BM) tumor cells before the start of treatment, at the time of best response and at relapse, we will follow the clonal composition and will detect the emergence of genetic resistance during treatment with BRAF and/or MEK inhibitor. We hypothesize that as MM cells become resistant to BRAF/MEK inhibition they rewire their cellular networks in order to generate adaptive changes that allow them to tolerate BRAF and/or MEK inhibition. We further postulate that cells from the BM microenvironment play a role in inducing these adaptive changes. To determine such mechanisms of adaptive resistance, we will characterize the transcriptional changes of MM cells and BM bystander cells using highly sensitive single cell RNA-sequencing. The work we propose is significant as it will track and define the mechanisms of drug resistance to BRAF/MEK inhibitors with unprecedented resolution, in the context of an innovative clinical trial that aims to establish BRAF/MEK inhibition as a novel treatment for patients with MM. This will help to understand if and why patients stop responding to BRAF/MEK inhibition, or if they do not respond to treatment in the first place. Since BRAF/MEK inhibitors will be given in the context of resistance to standard combination therapy (including proteasome inhibitors, IMiDs, alkylating agents), this approach will also inform why patients stop responding to standard therapy. By investigating the central role of BRAF/MAPK in oncogenesis, findings may be also translated to various other tumor entities carrying mutations in the BRAF gene such as anaplastic thyroid cancer, melanoma and hairy cell leukemia.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Jens Lohr, Ph.D.