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 *H.W., M.B. and M.K. shared co-senior authorship Additional Supporting Information may be found in the online version of this article. Molecular Cancer Biologyradioresistance 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 (TCD 50 ) was calculated. The TCD 50 for KRASwt/TP53mut xenografts was 43.1 Gy whereas KRASmut/TP53mut tumors required a 1.9-fold higher TCD 50 of 81.4 Gy. The EGFR inhibitor erlotinib radiosensitized KRASmut but not KRASwt cells and xenografts. The TCD 50 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. What's new?Clinical data linked co-mutation of the KRAS GTPase and the p53 tumor suppressor to radioresistance but rigorous pre-clinical studies have not been conducted. Here the authors validated these studies in mice and found that for local control of co-mutated non-small cell lung carcinoma xenografts an approximately two-fold higher dose of radiotherapy was required compared to wild-type tumors. Interestingly, pharmacological inhibition of epidermal growth factor receptor signaling sensitized co-mutated tumors to radiotherapy, underscoring the validity of the genotype as biomarker with therapeutic consequences.