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

V211D Mutation in MEK1 Causes Resistance to MEK Inhibitors in Colon Cancer.


Gao, Y. et al.
Cancer Discovery (2019)
Abstract

We report the emergence of the novel gatekeeper mutation in a patient with colon cancer treated with the allosteric MEK inhibitor binimetinib and the anti-EGFR antibody panitumumab. The mutation concurrently occurs in the same cell with and leads to RAF-independent activity but remains regulated by RAF. The V211D mutation causes resistance to binimetinib by both increasing the catalytic activity of MEK1 and reducing its affinity for the drug. Moreover, the mutant exhibits reduced sensitivity to all the allosteric MEK inhibitors tested. Thus, this mutation serves as a general resistance mutation for current MEK inhibitors; however, it is sensitive to a newly reported ATP-competitive MEK inhibitor, which therefore could be used to overcome drug resistance. SIGNIFICANCE: We report a resistance mechanism to allosteric MEK inhibitors in the clinic. A mutation developed in a patient with colon cancer on MEK and EGFR inhibitors. This mutant increases the catalytic activity of MEK1 and reduces its affinity for binimetinib, but remains sensitive to ATP-competitive MEK inhibitors..



Authors

Gao, Y., Maria, A., Na, N., da Cruz Paula, A., Gorelick, A.N., Hechtman, J.F., Carson, J., Lefkowitz, R.A., Weigelt, B., Taylor, B.S., Zhao, H., Reis-Filho, J.S., de Stanchina, E., Rosen, N., Yao, Z., Yaeger, R.



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)