RT Journal Article SR Electronic T1 TP53 null mutations identify lung cancer cell lines with highest sensitivity to the non-taxane microtubule inhibitor, eribulin JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP MOLPHARM-AR-2021-000254 DO 10.1124/molpharm.121.000254 A1 Trista K. Hinz A1 Roshni Kalkur A1 Jonathan Rabinovitch A1 Wyatt Hinkle A1 Lynn E. Heasley YR 2021 UL http://molpharm.aspetjournals.org/content/early/2021/05/24/molpharm.121.000254.abstract AB The non-taxane microtubule inhibitor, eribulin, is an approved therapeutic for metastatic breast cancer and liposarcoma. Eribulin was previously tested in unselected lung cancer patients and yielded a modest objective response rate of ~5-12 percent. 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) amongst 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 CDKN2A, STK11 and KEAP1 were not associated with eribulin sensitivity. Finally, the highest eribulin IC50 quartile (>~1 nM) exhibited significantly elevated mRNA expression of the drug pump, ABCB1, a defined resistance mechanism to eribulin and paclitaxel. The findings support further investigations into basic mechanisms by which complete lack of TP53 function regulates anti-cancer activity of eribulin and the potential utility of TP53 null phenotypes distinct from TP53 missense mutations as a biomarker of response in lung cancer patients. 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.