Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma.
Acquired resistance to targeted drugs is emerging as an obstacle to successful cancer treatment. Recently, a BCL2-selective BH3 mimetic termed ABT-199 showed promising therapeutic results in BCL2-dependent tumors. Based on its high affinity for BCL2, we studied potential mechanisms conferring resistance upon ABT-199 therapy, aiming to anticipate its occurrence in the clinic. Two models of resistant lymphomas were established by continuous ABT-199 exposure. In resistant Bcl2-expressing mouse lymphoma cells, 2 missense mutations within the Bcl2 BH3 domain were identified. Both F101C and F101L mutations impeded ABT-199 binding to the BH3 domain, therefore suppressing mitochondrial apoptosis. In resistant human lymphoma cells, a missense mutation in the C-terminal transmembrane domain of proapoptotic BAX (G179E) was found, which abrogated BAX anchoring to mitochondria and blocked ABT-199-induced apoptosis both in vitro and in vivo. Importantly, G179E BAX mutation also induced partial cross-resistance to other antineoplastic drugs. Our study reveals the acquisition of mutations in BCL2 family proteins as a novel mechanism of apoptosis resistance in cancer. These results anticipate the potential development of such mutations in patients treated with ABT-199, providing a basis to preventing their occurrence and to designing drugs able to circumvent the acquired resistance.
Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain; and.
Vicente
V
Fresquet
Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain; and.
Melissa
M
Rieger
Centre for Genomic Regulation and Pompeu Fabra University, Barcelona, Spain.
Carlo
C
Carolis
Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain; and.
Maria J
MJ
García-Barchino
Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain; and.
Jose A
JA
Martinez-Climent
D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D013449:Sulfonamides / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; C494826:BAX protein, human; C494827:Bax protein, mouse; D019086:Bridged Bicyclo Compounds, Heterocyclic; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; C579720:venetoclax