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Acquired resistance to PRMT5 inhibition induces concomitant collateral sensitivity to paclitaxel
Helen S Mueller1,2, Colin E Fowler1,2, Simona Dalin1,2
1The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Abstract:
Epigenetic regulators play key roles in cancer and are increasingly being targeted for treatment. However, for many, little is known about mechanisms of resistance to the inhibition of these regulators. We have generated a model of resistance to inhibitors of protein arginine methyltransferase 5 (PRMT5). This study was conducted in KrasG12D;Tp53-null lung adenocarcinoma (LUAD) cell lines. Resistance to PRMT5 inhibitors (PRMT5i) arose rapidly, and barcoding experiments showed that this resulted from a drug-induced transcriptional state switch, not selection of a preexisting population. This resistant state is both stable and conserved across variants arising from distinct LUAD lines. Moreover, it brought with it vulnerabilities to other chemotherapeutics, especially the taxane paclitaxel. This paclitaxel sensitivity depended on the presence of stathmin 2 (STMN2), a microtubule regulator that is specifically expressed in the resistant state. Remarkably, STMN2 was also essential for resistance to PRMT5 inhibition. Thus, a single gene is required for both acquisition of resistance to PRMT5i and collateral sensitivity to paclitaxel in our LUAD cells. Accordingly, the combination of PRMT5i and paclitaxel yielded potent and synergistic killing of the murine LUAD cells. Importantly, the synergy between PRMT5i and paclitaxel also extended to human cancer cell lines. Finally, analysis of The Cancer Genome Atlas patient data showed that high STMN2 levels correlate with complete regression of tumors in response to taxane treatment. Collectively, this study reveals a recurring mechanism of PRMT5i resistance in LUAD and identifies collateral sensitivities that have potential clinical relevance.
Insights
Resistance to protein arginine methyltransferase 5 inhibitors (PRMT5i) in lung adenocarcinoma involves a transcriptional switch. This switch confers sensitivity to paclitaxel, mediated by stathmin 2 (STMN2), offering a potential therapeutic combination.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Epigenetic regulators are crucial in cancer development and therapeutic targeting.
- Mechanisms of resistance to epigenetic drugs, particularly PRMT5 inhibitors, are not well understood.
- Lung adenocarcinoma (LUAD) presents a significant challenge due to treatment resistance.
Purpose of the Study:
- To investigate the mechanisms of resistance to protein arginine methyltransferase 5 inhibitors (PRMT5i) in KrasG12D;Tp53-null LUAD.
- To identify potential vulnerabilities or collateral sensitivities arising from PRMT5 inhibition resistance.
- To explore the therapeutic potential of combining PRMT5i with other agents.
Main Methods:
- Generation of a cellular model for PRMT5 inhibitor resistance in LUAD cell lines.
- Barcoding experiments to distinguish drug-induced states from pre-existing resistant populations.
- Analysis of gene expression changes, focusing on microtubule regulators like STMN2.
- Combination therapy studies in murine and human LUAD cell lines.
- Correlation analysis with The Cancer Genome Atlas (TCGA) patient data.
Main Results:
- Rapid resistance to PRMT5i emerged via a drug-induced transcriptional state switch, not clonal selection.
- This resistant state was stable, conserved across LUAD variants, and conferred sensitivity to paclitaxel.
- Stathmin 2 (STMN2) was identified as essential for both PRMT5i resistance and paclitaxel sensitivity.
- Combination of PRMT5i and paclitaxel demonstrated potent synergistic cytotoxicity in LUAD models.
- High STMN2 expression correlated with tumor regression in patients treated with taxanes.
Conclusions:
- A recurring mechanism of PRMT5i resistance in LUAD involves a transcriptional state switch mediated by STMN2.
- STMN2 is a critical mediator of both resistance to PRMT5i and collateral sensitivity to paclitaxel.
- The combination of PRMT5i and paclitaxel shows significant therapeutic potential for LUAD.
- STMN2 levels may serve as a predictive biomarker for taxane response in cancer patients.
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