Abstract 1944: Using patient-derived cancer organoids to determine the effects of the anti-EGFR therapy panitumumab in the presence or absence of <i>KRAS</i> mutation
Authors: Jordan N. Stoecker, Shirsa Udgata, Amani A. Gillette, Cheri A. Pasch, Melissa C. Skala, Dustin A. Deming
Journal: Cancer Research (2024)

Abstract Introduction: Tumor heterogeneity is a major cause of resistance to therapies in colorectal cancer (CRC). The anti-EGFR (epidermal growth factor receptor) therapies panitumumab (pani) and cetuximab, are now being investigated for the retreatment of patients when resistant subclones could be more abundant in a previously wild-type cancer. Here we utilize patient-derived cancer organoids (PDCOs) to investigate the potential implications of the abundance of resistant subclones on treatment and duration of response. Methods: Two CRC PDCO lines, one pani sensitive (PS) and one pani resistant (PR), were cultured separately and then mixed to determine how different combinations of mutations altered the time for the overall culture to be resistant to pani. NGS was performed on these cells to determine the mutation profile. The two PDCO lines were cultured together with the following concentrations (v/v) of 100% PS; 20% PR+80% PS; 10% PR+90% PS, 5% PR+95% PS, 1% PR+99% PS, and 100% PR using Matrigel and fed with previously published CRC organoid media. Widefield imaging was performed for diameter change analysis at day 0 and day 4 using ImageJ. Upon a median growth of &amp;gt;20% at baseline/untreated, all mixed populations were treated at increments of 20% physiologic Cmax of pani each week. Once select mixed populations reached 100% Cmax and maintained a median growth of &amp;gt;20% for two consecutive weeks, they were determined to have reached complete resistance to the treatment. Results: DNA sequencing of PDCOs showed PR has mutations associated with pani resistance (KRASG12V, PIK3CAH1047R) and the PS line did not. All the conditions except for 100% PS escalated to ≥40% Cmax within 7 weeks and reached complete resistance to pani by week 22. 100% PS remained at 20% Cmax through week 22. The 100% PR population reached complete resistance to pani the quickest at 100% Cmax at week 8. The conditions with the lowest percentages of PR (5% PR+95% PS and 1% PR+99% PS already started to show resistance above the PS line by 8 weeks and reached complete resistance to pani at week 12. Conclusion: PDCO lines containing low concentrations of resistant clones can quickly lead to resistance to pani treatment, even below the typical level for clinical NGS detection. All KRAS mutant conditions (PR) reached resistance quicker than 100% PS condition. Further studies will evaluate even low concentrations of resistance clones across further CRC PDCO models and will evaluate the mechanism by which these clones are leading to resistance. Citation Format: Jordan N. Stoecker, Shirsa Udgata, Amani A. Gillette, Cheri A. Pasch, Melissa C. Skala, Dustin A. Deming. Using patient-derived cancer organoids to determine the effects of the anti-EGFR therapy panitumumab in the presence or absence of KRAS mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1944.