Abstract 1101: CTNNB1 mutation can mediate resistance to EGFR, ALK and KRAS targeted therapies

Abstract Resistance to targeted therapy remains an ongoing and elusive challenge in lung cancer. β-Catenin (CTNNB1) mutations have been reported in lung cancer patients, often co-occurring with known oncogenic drivers such as rearranged ALK, and mutant EGFR and KRAS. Oncogenic CTNNB1 mutations result in aberrant accumulation of the encoded β-catenin protein and may cause resistance to targeted therapy. However, different CTNNB1 mutations may activate β-catenin differentially and thereby have varying phenotypic effects. A CTNNB1 T41A mutation was identified in donated lung cancer tissue from a patient with a clinical history of an EGFR exon 20 insertion. To investigate the functional significance of this mutation, CTNNB1 T41A was transduced into an EGFR-mutated cell line (HCC827) and one cell line harboring ALK translocation (STE1). Response to EGFR and ALK targeted therapy was then compared in the GFP-transduced control cell lines versus the CTNNB1 T41A transduced cell lines to assess for effects of this CTNNB1 mutation on targeted therapy. Both HCC827 and STE1 cells harboring the CTNNB1 T41A mutation were more resistant to EGFR and ALK targeted therapy than the control cell lines. Since, different CTNNB1 mutations may exert different phenotypic effects, the CTNNB1 mutation spectrum was analyzed in lung cancer patients at the Moffitt Cancer Center. Mutations in 19 unique residues of CTNNB1 (D32, S33, G34, S37, T41, S45, A215, C419, S29, G757, K335, N287, Q72, R151, R710, S352, S681, V62 and W383) were detected in 50 lung cancer patients. Of these, 23 had some type of EGFR abnormality that co-existed with the CTNNB1 mutation while others had ROS1, RET, BRAF, NTRK3, ALK or KRAS mutations. The most frequent Exon 3 hotspot CTNNB1 mutations (at residues D32, S33, G34, S37, and S45) were chosen for further analysis wherein these mutations were transduced into HCC827, STE1 and two KRAS mutant cell lines (H358 and LU65) to assess their ability to drive resistance to EGFR, ALK and KRAS targeted therapies in ongoing studies. Our data shows that CTNNB1 mutations can cause resistance to EGFR, ALK and KRAS inhibitor therapy to different extents. Hence, further investigation of the mechanism of action of these beta-catenin mutations and the ability of beta-catenin/other inhibitors to reverse resistance is needed. This data also suggests that CTNNB1 may be an important co-occurring alteration in the context of development of resistance to targeted therapy and should be included in comprehensive clinical genetic testing panels. Citation Format: Anurima Majumder, Benjamin S. Meyer, J Kevin Hicks, Theresa A. Boyle, Eric B. Haura. CTNNB1 mutation can mediate resistance to EGFR, ALK and KRAS targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1101.