Biology subjects

Peterson, J. L.

Publications and source records attributed to Peterson, J. L..

3 recordsLinked to original sources

bioRxiv2026

Prevalence and Actionability of MTAP Loss in Oncogene-Driven Lung Cancer

BackgroundMethylthioadenosine phosphorylase (MTAP) loss co-occurs with actionable genomic alterations in non-small cell lung cancer (NSCLC) and creates vulnerability to protein arginine methyltransferase 5 (PRMT5) inhibition. Estimates of prevalence of MTAP loss rely on next-generation sequencing which can underestimate copy losses. Moreover, the activity of PRMT5 inhibitors in oncogene-driven NSCLC is not well established. MethodsWe assessed MTAP expression by immunohistochemistry (IHC) in 243 NSCLCs (n=132 early stage, n=111 metastatic), including 33 specimens with paired lymph nodes. Antiproliferative activity of PRMT5 inhibitor monotherapy and in combination with tyrosine kinase inhibitors (TKIs) was evaluated in MTAP-deleted NSCLC cell lines harboring EGFR or KRAS mutations or ALK rearrangements. ResultsAmong 243 NSCLC specimens from 240 patients (72% with driver alterations, 90% adenocarcinoma), MTAP loss was identified in 43 (18%) specimens from 40 (17%) patients, including 18 (14%) early-stage and 22 (20%) metastatic tumors. MTAP loss occurred in 24% of stage 4 driver-positive NSCLCs versus 14% of driver-negative tumors (p=0.314). Twenty (61%) lung-nodal pairs demonstrated concordance; eight cases only exhibited decreased MTAP expression in nodes. Variable sensitivity to PRMT5 inhibitors was observed in 22 MTAP-deleted NSCLC cell lines (9 EGFR-mutant, 7 KRAS-mutant, 6 ALK-rearranged), with responses seen in TKI-sensitive and TKI-resistant lines. SDMA (symmetric dimethylarginine) expression did not predict PRMT5 inhibitor sensitivity. TKI + PRMT5 inhibitor combos had greater activity than monotherapy. ConclusionsMTAP loss occurs in 1-in-5 oncogene-driven metastatic NSCLCs. PRMT5 inhibitor activity is independent of TKI exposure, driver alteration, and SDMA expression and enhanced by addition of TKI. These findings support clinical evaluation of PRMT5 inhibitor + TKI combinations for advanced NSCLC.

cancer biology↗

bioRxiv2021

Structural and functional analysis of lorlatinib analogs reveals roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer

The treatment approach to advanced, ALK-positive non-small cell lung cancer (NSCLC) utilizing sequential ALK tyrosine kinase inhibitors (TKIs) represents a paradigm of precision oncology. Lorlatinib is currently the most advanced, potent and selective ALK tyrosine kinase inhibitor (TKI) in the clinic. However, tumors invariably acquire resistance to lorlatinib, and after sequential ALK TKIs culminating with lorlatinib, diverse refractory compound ALK mutations can emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations identified in patients after treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. By assessing a panel of lorlatinib analogs against compound ALK mutant in vitro and in vivo models, we identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R- versus I1171N/S/T-based compound ALK mutations. Structural analysis revealed that increased potency against compound mutations was achieved primarily through two different mechanisms of improved targeting of either G1202R- or I1171N/S/T-mutant kinases. Based on these results, we propose a classification of heterogenous ALK compound mutations designed to focus the development of distinct therapeutic strategies for precision targeting of compound resistance mutations following sequential TKIs.

cancer biology↗

bioRxiv2020

Accurate imputation of histone modifications using transcription

The role of histone modifications in transcription remains incompletely understood. Here we used experimental perturbations combined with sensitive machine learning tools that infer the distribution of histone marks using maps of nascent transcription. Transcription predicted the variation in active histone marks and complex chromatin states, like bivalent promoters, down to single-nucleosome resolution and at an accuracy that rivaled the correspondence between independent ChIP-seq experiments. Blocking transcription rapidly removed two punctate marks, H3K4me3 and H3K27ac, from chromatin indicating that transcription is required for active histone modifications. Transcription was also required for maintenance of H3K27me3 consistent with a role for RNA in recruiting PRC2. A subset of DNase-I hypersensitive sites were refractory to prediction, precluding models where transcription initiates pervasively at any open chromatin. Our results, in combination with past literature, support a model in which active histone modifications serve a supportive, rather than a regulatory, role in transcription.

genomics↗