Abboud, A. | bioRxiv Science

bioRxiv2026

Real-World Progression-Free Survival with Erlotinib versus Osimertinib in EGFR L858R+T790M Compound Mutation Non-Small Cell Lung Cancer: An Exploratory Analysis of the MSK-CHORD Dataset

BackgroundOsimertinib is the standard first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC) harboring common activating mutations, including exon 19 deletions and L858R. It is also active against tumors with acquired T790M resistance. However, the EGFR L858R+T790M compound mutation -- where both variants co-occur within the same tumor -- may confer distinct drug-sensitivity profiles not predicted by either mutation alone. Limited data exist on comparative treatment outcomes in this rare genotype. MethodsUsing the MSK-CHORD clinicogenomic dataset (n=24,950), we identified patients with concurrent EGFR L858R and T790M mutations receiving erlotinib (Erlo) or osimertinib (Osi) monotherapy. Real-world progression-free survival (rwPFS) per treatment line was calculated using a strict definition requiring confirmed radiological progression events (rwPFS-strict), excluding lines with null endpoint data. Kaplan-Meier analysis, log-rank testing, Cox proportional hazards regression, and cross-cohort heterogeneity testing (Cochrans Q statistic) were performed. Two control cohorts -- L858R-only (n=372) and T790M-only (n=76) -- were analyzed in parallel to assess mutation-context specificity of treatment response. ResultsThirty-one patients with EGFR L858R+T790M were identified; 21 contributed evaluable monotherapy lines, yielding 23 Erlo and 15 Osi treatment lines (14 unique patients per treatment group, 7 contributing to both). Median rwPFS numerically favored Erlo over Osi (7.10 vs 5.32 months; HR 1.29, 95% CI 0.66-2.52; log-rank p=0.46). This directional trend was reversed in the L858R-only control cohort, where Osi demonstrated significant superiority (9.03 vs 5.75 months; HR 0.70, 95% CI 0.55-0.89; p=0.003). The T790M-only cohort showed no significant difference (HR 1.32, p=0.12). An exploratory post-hoc heterogeneity test confirmed a significant cross-cohort interaction (Q=9.94, df=2, p=0.007). ConclusionsThe expected osimertinib advantage was absent in L858R+T790M compound-mutant NSCLC. The opposing hazard ratio directions across mutation contexts (HR 1.29 vs 0.70), with a significant exploratory cross-cohort interaction (p=0.007), suggest that the EGFR L858R+T790M compound mutation may represent a pharmacologically distinct entity with differential TKI sensitivity. These hypothesis-generating findings warrant prospective validation. HIGHLIGHTSO_LIL858R+T790M compound mutation may represent a distinct pharmacological TKI context. C_LIO_LIErlotinib showed a point-estimate PFS advantage over osimertinib (HR 1.29, p=0.46). C_LIO_LIOsimertinib was significantly superior in L858R-only disease (HR 0.70, p=0.003). C_LIO_LICross-cohort HR reversal in T790M-containing cohorts; interaction p=0.007. C_LIO_LIProspective validation with larger cohorts and allelic phasing data is warranted. C_LI TWEETABLE ABSTRACT#EGFR L858R+T790M compound mutation: erlotinib trend over osimertinib (HR 1.29 vs 0.70 in L858R-only), interaction p=0.007. #LungCancer

bioinformatics↗

bioRxiv2018

Dynamics-function relationship of N-terminal acetyltransferases: the β6β7 loop modulates substrate accessibility to the catalytic site

N-terminal acetyltransferases (NATs) are enzymes catalysing the transfer of the acetyl from Ac-CoA to the N-terminus of proteins, one of the most common protein modifications. Unlike NATs, lysine acetyltransferases (KATs) transfer an acetyl onto the amine group of internal lysines. To date, not much is known on the exclusive substrate specificity of NATs towards protein N-termini. All the NATs and some KATs share a common fold called GNAT. The main difference between NATs and KATs is an extra hairpin loop found only in NATs called {beta}6{beta}7 loop. It covers the active site as a lid. The hypothesized role of the loop is that of a barrier restricting the access to the catalytic site and preventing acetylation of internal lysines. We investigated the dynamics-function relationships of all available structures of NATs covering the three domains of life. Using elastic network models and normal mode analysis, we found a common dynamics pattern conserved through the GNAT fold; a rigid V-shaped groove, formed by the {beta}4 and {beta}5 strands and three relatively more dynamic loops 12, {beta}3{beta}4 and {beta}6{beta}7. We identified two independent dynamical domains in the GNAT fold, which is split at the {beta}5 strand. We characterized the {beta}6{beta}7 hairpin loop slow dynamics and show that its movements are able to significantly widen the mouth of the ligand binding site thereby influencing its size and shape. Taken together our results show that NATs may have access to a broader ligand specificity range than anticipated.\n\nAuthor summaryN-terminal acetylation concerns 80% of eukaryotic proteins and is achieved by enzymes called the N-terminal acetyltransferases (NATs). They belong to the large family of acetyltransferases and adopt the GNAT fold. Interestingly most lysine acetyltransferases (KATs), which acetylate specifically internal lysines, share the same fold. Rationale for the ligand recognition by the GNAT enzymes remains unclear. Proteins are dynamic entities that utilize their structural flexibility to carry out functions in living cells. By studying the dynamics throughout the entire NATs family, we found that the slow dynamics of the fold is strongly conserved. We also revealed the mobility of the active site lid, namely the {beta}-hairpin loop {beta}6{beta}7, which is one of the main structural differences between the NATs and the KATs. The size and shape of the ligand binding site depend on movements of that {beta}-hairpin loop. We suggest that in attempts of mapping NATs specificity or ligand design the fold flexibility should be taken into consideration.

bioinformatics↗