Biology subjects

Piotrowska, Z.

Publications and source records attributed to Piotrowska, Z..

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

APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer

Acquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1-6, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes7 or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones8 remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number alterations and structural variations. Preventing therapy-induced A3A mutagenesis either by gene deletion or RNAi-mediated suppression delayed the emergence of drug resistance. Finally, we observed accumulation of A3A mutations in lung cancer patients who developed drug resistance after treatment with sequential targeted therapies. These data suggest that induction of A3A mutagenesis in response to targeted therapy treatment may facilitate the development of acquired resistance in non-small-cell lung cancer. Thus, suppressing expression or enzymatic activity of A3A may represent a potential therapeutic strategy to prevent or delay acquired resistance to lung cancer targeted therapy.

cancer biology↗

bioRxiv2019

Modeling Resistance and Recurrence Patterns of Combined Targeted- Chemoradiotherapy Predicts Benefit of Shorter Induction Period

The optimal integration of molecularly targeted therapies with concurrent chemotherapy and radiation (CRT) to improve cures in genotype-defined cancers is unknown. Here, we develop a bio-mathematical framework to simulate patterns of local versus distant recurrences in a heterogeneous lung cancer population receiving combined targeted therapy and CRT. Our validated model predicts that targeted induction before CRT, an approach currently being tested in clinical trials, may render adjuvant targeted therapy less effective due to proliferation of drug-resistant cancer cells when using very long induction periods. Furthermore, our simulations not only demonstrate the competing effects of drug-resistant cell expansion versus overall tumor regression as a function of induction length, but can also directly estimate the probability of observing an improvement in progression-free survival at a given cohort size. We thus demonstrate that such stochastic biological simulations have the potential to quantitatively inform the design of multimodality clinical trials in genotype-defined cancers.

biophysics↗