TP53 Null Mutations Identify Lung Cancer Cell Lines with Highest Sensitivity to the Nontaxane Microtubule Inhibitor Eribulin.

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.

• Authors: Trista K Hinz, Roshni Kalkur, Jonathan Rabinovitch, Wyatt Hinkle, Lynn E Heasley
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 100 Issue 2 Pg. 144-154 (08 2021) ISSN: 1521-0111 [Electronic] United States
• PMID: 34031188 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Furans
• Ketones
• TP53 protein, human
• Tumor Suppressor Protein p53
• eribulin

Topics

• A549 Cells
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Carcinoma, Small Cell (drug therapy, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Furans (pharmacology)
• Gene Expression Regulation, Neoplastic
• Humans
• Inhibitory Concentration 50
• Ketones (pharmacology)
• Loss of Function Mutation
• Lung Neoplasms (drug therapy, genetics)
• Precision Medicine
• Tumor Suppressor Protein p53 (genetics)