Venetoclax resistance leads to broad resistance to standard-of-care anti-MM agents, but not to immunotherapies
Year: 2024
Type: article
Abstract: ABSTACT: To our knowledge, venetoclax is the first example of personalized medicine for multiple myeloma (MM), with meaningful clinical activity as a monotherapy and in combination in patients with myeloma harboring the t(11:14) translocation. However, despite the high response rates and prolonged progression-free survival, a significant proportion of patients eventually relapse. Here, we aim to study adaptive molecular responses after the acquisition of venetoclax resistance in sensitive t(11:14) MM cell models. We therefore generated single-cell venetoclax-resistant t(11:14) MM cell lines and investigated the mechanisms contributing to resistance as well as the cells' sensitivity to other treatments. Our data suggest that acquired resistance to venetoclax is characterized by reduced mitochondrial priming and changes in B-cell lymphoma-2 (BCL-2) family proteins' expression in MM cells, conferring broad resistance to standard-of-care antimyeloma drugs. However, our results show that the resistant cells are still sensitive to immunotherapeutic treatments, highlighting the need to consider appropriate sequencing of these treatments after venetoclax-based regimens.
Source: Blood Advances
Authors: Shuhui Deng, Sanika Derebail, Vera Joy Weiler, Jessica Fong Ng, Elena Maroto-Martin, Madhumouli Chatterjee, Giulia Giorgetti, Chandraditya Chakraborty, Poonam Kalhotra, Ting Du, Yao Yao, Rao Prabhala, Masood Shammas, Annamaria Gulla, Anil Aktas Samur, Mehmet Kemal Samur, Lugui Qiu, Kenneth C. Anderson, Mariateresa Fulciniti, Nikhil C. Munshi
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,000
OpenAlex ID: W4399532431