Functional measurement of mitogen-activated protein kinase pathway activation predicts responsiveness of RAS-mutant cancers to MEK inhibitors
In: European Journal of Cancer, Jg. 149 (2021-05-01), S. 184-192
Online
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Zugriff:
Background RAS variant–related functional impact on the mitogen-activated protein kinase (MAPK) pathway, and correlation between MAPK activation and MAPK/ERK kinase (MEK) inhibitor responsiveness, is not established. Patients and methods Of 1,693 tumours sequenced, 576 harboured a RAS alteration; 62 patients received an MEK inhibitor (MEKi) and had RAS mutations that were functionally characterised. We report that RAS mutants have variable levels of MAPK activity, as measured by a functional cell-based assay that quantified MAPK pathway activation after transfection with a variety of RAS mutations. Results Patients with tumours harbouring RAS alterations with high versus low MAPK activity who were treated with an MEKi showed significantly longer median progression-free survival (PFS) (5.0 vs. 2.3 months; p = 0.0034) and overall survival (20.0 vs. 5.0 months; p = 0.0146) and a trend towards higher rates of clinical benefit (stable disease ≥6 months or partial/complete remission) (38% versus 15%; p = 0.095) (p-values as per univariate analysis). PFS remained statistically significant after the multivariate analysis (p = 0.003). Conclusions These results support a correlation between RAS-mutant cancers with greater MAPK signalling and PFS after MEKi treatment.
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Functional measurement of mitogen-activated protein kinase pathway activation predicts responsiveness of RAS-mutant cancers to MEK inhibitors
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Autor/in / Beteiligte Person: | Tarcic, Gabi ; Kurzrock, Razelle ; Zelichov, Ori ; Kato, Shumei ; Lee, Suzanna ; Vidne, Michael ; Okamura, Ryosuke ; Porter, Robert |
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Zeitschrift: | European Journal of Cancer, Jg. 149 (2021-05-01), S. 184-192 |
Veröffentlichung: | Elsevier BV, 2021 |
Medientyp: | unknown |
ISSN: | 0959-8049 (print) |
DOI: | 10.1016/j.ejca.2021.01.055 |
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