Radioresistance of KRAS/TP53-mutated lung cancer can be overcome by radiation dose escalation or EGFR tyrosine kinase inhibition in vivo.

ABSTRACT: Recent clinical data have linked KRAS/TP53 comutation (mut) to resistance to radiotherapy (RT), but supporting laboratory in vivo evidence is lacking. In addition, the ability of different radiation doses, with/without epidermal growth factor receptor (EGFR)-directed treatment, to achieve local tumor control as a function of KRAS status is unknown. Here, we assessed clonogenic radiation survival of a panel of annotated lung cancer cell lines. KRASmut/TP53mut was associated with the highest radioresistance in nonisogenic and isogenic comparisons. To validate these findings, isogenic TP53mut NCI-H1703 models, KRASmut or wild-type (wt), were grown as heterotopic xenografts in nude mice. A clinical RT schedule of 30 fractions over 6 weeks was employed. The dose that controlled 50% of tumors (TCD₅₀ ) was calculated. The TCD₅₀ for KRASwt/TP53mut xenografts was 43.1 Gy whereas KRASmut/TP53mut tumors required a 1.9-fold higher TCD₅₀ of 81.4 Gy. The EGFR inhibitor erlotinib radiosensitized KRASmut but not KRASwt cells and xenografts. The TCD₅₀ associated with adding erlotinib to RT was 58.8 Gy for KRASmut, that is, a ~1.4-fold dose enhancement. However, the EGFR antibody cetuximab did not have a radiosensitizing effect. In conclusion, we demonstrate for the first time that KRASmut in a TP53mut background confers radioresistance when studying a clinical RT schedule and local control rather than tumor growth delay. Despite the known unresponsiveness of KRASmut tumors to EGFR inhibitors, erlotinib radiosensitized KRASmut tumors. Our data highlight KRAS/TP53 comutation as a candidate biomarker of radioresistance that can be at least partially reversed by dose escalation or the addition of a targeted agent.

SUBMITTER: Gurtner K 

PROVIDER: S-EPMC7440664 | biostudies-literature |

REPOSITORIES: biostudies-literature