Thank you! Your submission has been received!
Oops! Something went wrong while submitting the form.
X
Mission Bio Blog and Podcast go live! Get the latest news and trends on single-cell multi-omics. Subscribe
X
publication

Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML.


Choe, S. et al.
Blood Advances (2020)
Abstract

Isocitrate dehydrogenase (IDH) 1 and 2 mutations result in overproduction of D-2-hydroxyglutarate (2-HG) and impaired cellular differentiation. Ivosidenib, a targeted mutant IDH1 (mIDH1) enzyme inhibitor, can restore normal differentiation and results in clinical responses in a subset of patients with mIDH1 relapsed/refractory (R/R) acute myeloid leukemia (AML). We explored mechanisms of ivosidenib resistance in 174 patients with confirmed mIDH1 R/R AML from a phase 1 trial. Receptor tyrosine kinase (RTK) pathway mutations were associated with primary resistance to ivosidenib. Multiple mechanisms contributed to acquired resistance, particularly outgrowth of RTK pathway mutations and 2-HG-restoring mutations (second-site IDH1 mutations, IDH2 mutations). Observation of multiple concurrent mechanisms in individual patients underscores the complex biology of resistance and has important implications for rational combination therapy design. This trial was registered at www.clinicaltrials.gov as #NCT02074839.



Authors

Choe, S., Wang, H., DiNardo, C.D., Stein, E.M., de Botton, S., Roboz, G.J., Altman, J.K., Mims, A.S., Watts, J.M., Pollyea, D.A., Fathi, A.T., Tallman, M.S., Kantarjian, H.M., Stone, R.M., Quek, L., Konteatis, Z., Dang, L., Nicolay, B., Nejad, P., Liu, G., Zhang, V., Liu, H., Goldwasser, M., Liu, W., Marks, K., Bowden, C., Biller, S.A., Attar, E.C., Wu, B.



VIEW

publication
Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma
Marin-Bejar, O.
Cancer Cell (2021)
publication
Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias
Thijssen, R.
Blood (2021)
publication
Personalized single-cell proteogenomics to distinguish acute myeloid leukemia from nonmalignant clonal hematopoiesis
Dillon, L.W.
Blood Cancer Discovery (2021)
publication
PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism
Ren, A.A.
Nature (2021)