Leveraging Systematic Functional Analysis to Benchmark an In Silico Framework Distinguishes Driver from Passenger MEK Mutants in Cancer.

Abstract:

:Despite significant advances in cancer precision medicine, a significant hurdle to its broader adoption remains the multitude of variants of unknown significance identified by clinical tumor sequencing and the lack of biologically validated methods to distinguish between functional and benign variants. Here we used functional data on MAP2K1 and MAP2K2 mutations generated in real-time within a co-clinical trial framework to benchmark the predictive value of a three-part in silico methodology. Our computational approach to variant classification incorporated hotspot analysis, three-dimensional molecular dynamics simulation, and sequence paralogy. In silico prediction accurately distinguished functional from benign MAP2K1 and MAP2K2 mutants, yet drug sensitivity varied widely among activating mutant alleles. These results suggest that multifaceted in silico modeling can inform patient accrual to MEK/ERK inhibitor clinical trials, but computational methods need to be paired with laboratory- and clinic-based efforts designed to unravel variabilities in drug response. SIGNIFICANCE: Leveraging prospective functional characterization of MEK1/2 mutants, it was found that hotspot analysis, molecular dynamics simulation, and sequence paralogy are complementary tools that can robustly prioritize variants for biologic, therapeutic, and clinical validation.See related commentary by Whitehead and Sebolt-Leopold, p. 4042.

journal_name

Cancer Res

journal_title

Cancer research

authors

Hanrahan AJ,Sylvester BE,Chang MT,Elzein A,Gao J,Han W,Liu Y,Xu D,Gao SP,Gorelick AN,Jones AM,Kiliti AJ,Nissan MH,Nimura CA,Poteshman AN,Yao Z,Gao Y,Hu W,Wise HC,Gavrila EI,Shoushtari AN,Tiwari S,Viale A,Abd

doi

10.1158/0008-5472.CAN-20-0865

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

4233-4243

issue

19

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-20-0865

journal_volume

80

pub_type

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