American Association for Cancer Research
00085472can142073-sup-134667_1_supp_2660846_nbynzb.pdf (6.51 MB)

Supplemental Figures 1-8 from ERK Mutations Confer Resistance to Mitogen-Activated Protein Kinase Pathway Inhibitors

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posted on 2023-03-30, 22:48 authored by Eva M. Goetz, Mahmoud Ghandi, Daniel J. Treacy, Nikhil Wagle, Levi A. Garraway

Supplemental Figures 1-8. Fig. S1. The landscape of mutations of putative ERK1/2 resistance alleles; Fig. S2. Expression and signaling induced by validated ERK resistance alleles; Fig. S3. ERK2 signaling and kinase activity assays with the ERK inhibitor SCH772984; Fig. S4. Analysis of co-mutated ERK1/2 alterations; Fig. S5. Structural localization of RAF/MEK inhibitor alleles; Fig. S6. Drug sensitivity of non-validating alleles; Fig. S7. Drug sensitivity assays of RAF/MEK inhibitor resistance alleles; Fig. S8. Viability of ERK1/2 resistance alleles in WM266.4 cells



The use of targeted therapeutics directed against BRAFV600-mutant metastatic melanoma improves progression-free survival in many patients; however, acquired drug resistance remains a major medical challenge. By far, the most common clinical resistance mechanism involves reactivation of the MAPK (RAF/MEK/ERK) pathway by a variety of mechanisms. Thus, targeting ERK itself has emerged as an attractive therapeutic concept, and several ERK inhibitors have entered clinical trials. We sought to preemptively determine mutations in ERK1/2 that confer resistance to either ERK inhibitors or combined RAF/MEK inhibition in BRAFV600-mutant melanoma. Using a random mutagenesis screen, we identified multiple point mutations in ERK1 (MAPK3) and ERK2 (MAPK1) that could confer resistance to ERK or RAF/MEK inhibitors. ERK inhibitor–resistant alleles were sensitive to RAF/MEK inhibitors and vice versa, suggesting that the future development of alternating RAF/MEK and ERK inhibitor regimens might help circumvent resistance to these agents. Cancer Res; 74(23); 7079–89. ©2014 AACR.

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