Activation of the MAPK pathway mediates resistance to PI3K inhibitors in chronic lymphocytic leukemia
| Autor: | Gilad Itchaki, Svitlana Tyekucheva, Shuai Dong, Ignaty Leshchiner, Ishwarya Murali, Dimitri Livitz, Emily M. Thrash, Jasneet Kaur Khalsa, Amy J. Johnson, Gad Getz, Jennifer R. Brown, Stacey M. Fernandes, Siddha Kasar, Aishath S Naeem |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Adult
Male 0301 basic medicine MAPK/ERK pathway MAP Kinase Signaling System Chronic lymphocytic leukemia Immunology Biochemistry 03 medical and health sciences 0302 clinical medicine Cell Line Tumor hemic and lymphatic diseases medicine Humans Bruton's tyrosine kinase Extracellular Signal-Regulated MAP Kinases PI3K/AKT/mTOR pathway Aged Phosphoinositide-3 Kinase Inhibitors Quinazolinones biology Genome Human business.industry MEK inhibitor breakpoint cluster region Cell Biology Hematology Middle Aged medicine.disease Leukemia Lymphocytic Chronic B-Cell Up-Regulation Enzyme Activation Treatment Outcome 030104 developmental biology Drug Resistance Neoplasm Purines 030220 oncology & carcinogenesis Mutation Cancer research biology.protein Female Signal transduction business Idelalisib Proto-Oncogene Proteins c-akt |
| Zdroj: | Blood. 138:44-56 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Inhibitors of Bruton tyrosine kinase (BTK) and phosphatidylinositol 3-kinase δ (PI3Kδ) that target the B-cell receptor (BCR) signaling pathway have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Mutations associated with resistance to BTK inhibitors have been identified, but limited data are available on mechanisms of resistance to PI3Kδ inhibitors. Here we present findings from longitudinal whole-exome sequencing of cells from patients with multiply relapsed CLL (N = 28) enrolled in trials of PI3K inhibitors. The nonresponder subgroup was characterized by baseline activating mutations in MAP2K1, BRAF, and KRAS genes in 60% of patients. PI3Kδ inhibition failed to inhibit ERK phosphorylation (pERK) in nonresponder CLL cells with and without mutations, whereas treatment with a MEK inhibitor rescued ERK inhibition. Overexpression of MAP2K1 mutants in vitro led to increased basal and inducible pERK and resistance to idelalisib. These data demonstrate that MAPK/ERK activation plays a key role in resistance to PI3Kδ inhibitors in CLL and provide a rationale for therapy with a combination of PI3Kδ and ERK inhibitors. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|