TP53 Null Mutations Identify Lung Cancer Cell Lines with Highest Sensitivity to the Nontaxane Microtubule Inhibitor
Trista K Hinz1, Roshni Kalkur1, Jonathan Rabinovitch1
1Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado (T.K.H., R.K., J.R., W.H., L.E.H.) and Eastern Colorado VA Healthcare System, Rocky Mountain Regional VA Medical Center, Aurora, Colorado (L.E.H.).
Abstract:
The nontaxane microtubule inhibitor eribulin is an approved therapeutic for metastatic breast cancer and liposarcoma. Eribulin was previously tested in unselected patients with lung cancer and yielded a modest objective response rate of ∼5%-12%. Because lung cancers represent diverse histologies and driving oncogenic mutations, we postulated that eribulin may exhibit properties of a precision oncology agent with a previously undefined specificity for a molecularly distinct subset of lung cancers. Herein, we screened a panel of 44 non-small cell and small-cell lung cancer cell lines for in vitro growth sensitivity to eribulin. The results revealed a greater than 15,000-fold range in eribulin sensitivity (IC50 = 0.005-89 nM) among the cell lines that was not correlated with their sensitivity to the taxane-based inhibitor paclitaxel. The quartile of cell lines exhibiting the lowest eribulin IC50 values was not enriched for specific histologies, epithelial-mesenchymal differentiation, or specific oncogene drivers but was significantly enriched for nonsense/frameshift TP53 mutations and low-TP53 mRNA but not missense TP53 mutations. By comparison, the mutation status of cyclin-dependent kinase inhibitor 2A, STK11, and KEAP1 was not associated with eribulin sensitivity. Finally, the highest eribulin IC50 quartile (>1 nM) exhibited significantly elevated mRNA expression of the drug pump, ATP binding cassette B1, defined resistance mechanism to eribulin, and paclitaxel. The findings support further investigations into basic mechanisms by which complete lack of TP53 function regulates anticancer activity of eribulin and the potential utility of TP53 null phenotypes distinct from TP53 missense mutations as a biomarker of response in patients with lung cancer. SIGNIFICANCE STATEMENT: Distinct from precision oncology agents that are matched to cancers bearing oncogenically activated versions of their targets, microtubule inhibitors, such as eribulin, are deployed in an unselected manner. The results in this study demonstrate that lung cancer cell lines exhibiting the highest sensitivity to eribulin bear TP53 null phenotypes, supporting a rationale to consider the status of this tumor suppressor in the clinical setting.
Insights
Eribulin, a cancer drug, shows higher sensitivity in lung cancer cells with TP53 null mutations. This finding suggests TP53 status could be a biomarker for eribulin treatment response.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Eribulin is an approved nontaxane microtubule inhibitor for metastatic breast cancer and liposarcoma.
- Previous trials in unselected lung cancer patients showed modest response rates (5%-12%) for eribulin.
- Lung cancers exhibit diverse histologies and oncogenic mutations, suggesting potential for precision targeting.
Purpose of the Study:
- To investigate if eribulin acts as a precision oncology agent for a specific subset of lung cancers.
- To screen lung cancer cell lines for in vitro sensitivity to eribulin.
- To identify molecular features associated with eribulin sensitivity or resistance.
Main Methods:
- Screening of 44 non-small cell and small-cell lung cancer cell lines for in vitro growth sensitivity to eribulin.
- Analysis of eribulin sensitivity (IC50) and correlation with paclitaxel sensitivity.
- Genomic and transcriptomic analysis to identify associations with TP53 mutations, mRNA levels, and other gene statuses (CDKN2A, STK11, KEAP1).
Main Results:
- A wide range of eribulin sensitivity (IC50: 0.005-89 nM) was observed, independent of paclitaxel sensitivity.
- Highest eribulin sensitivity was significantly enriched in cell lines with nonsense/frameshift TP53 mutations (TP53 null phenotypes) and low TP53 mRNA.
- Elevated ATP binding cassette B1 (ABCB1) mRNA expression, a known resistance mechanism, was found in the least sensitive cell lines.
Conclusions:
- TP53 null phenotypes, characterized by complete loss of TP53 function, are associated with increased sensitivity to eribulin in lung cancer.
- TP53 mutation status, specifically null mutations, may serve as a predictive biomarker for eribulin response in lung cancer patients.
- Further research is warranted to elucidate the mechanisms of TP53's role in eribulin's anticancer activity and clinical utility.
