Abstract PO-118: Novel mechanisms of EGFR-TKI resistance and clonal evolution of lung adenocarcinoma by overexpression of a cell adhesion molecule, CADM1

Abstract

Abstract Evolution of cancer and generation of its heterogeneity are most dynamically demonstrated in the process of cancer cells acquiring resistance to molecular targeted therapy. Lung adenocarcinoma is the best solid tumor to which molecular targeted therapy is established and clinically available. However, tumors resistant against targeted drugs develop frequently, providing the biggest challenge in current treatment of lung adenocarcinoma. The tumors resistant to the initial treatment also show more malignant features, such as invasion and metastasis. Thus, it is interesting to investigate possible mechanisms to link EGFR-TKI resistance to malignant progression in lung adenocarcinoma. A cell adhesion molecule, CADM1, is originally identified as a tumor suppressor in lung adenocarcinoma. CADM1 is involved in the formation and maintenance of an epithelial cell structure. On the other hand, CADM1 is frequently inactivated by promoter methylation in various cancers in their advanced stages. In lung adenocarcinoma, CADM1 was expressed in the cell-cell attachment sites in lepidic growth components, whereas CADM1 expression was frequently lost in invasive lesions, conferring heterogenous features to cancer tissue. We have also reported that CADM1 inhibits HGF-induced epithelial mesenchymal transition of canine kidney cells, MDCK, by associating with MET and intervening with MET signaling on the cell membrane. Here, we demonstrate significant expression of CADM1 in a lung adenocarcinoma cell, HCC827, but not in its gefitinib-resistant derivatives, HCC827GR5 or GR6, which express significant amounts of phosphorylated MET (p-MET). Introducing CADM1 expression into HCC827GR5 restores the sensitivity to gefitinib in association with decreasing amount of pMET. In contrast, CADM1 is not effective at restoring gefitinib sensitivity in PC9 cells carrying T790M mutation of EGFR. Dox-inducible CADM1 expression in HCC827GR5 also showed restoration of gefitinib sensitivity both in vivo and in vitro. Finally, intra-tumoral injection of adenoviruses expressing CADM1, but not control adenoviruses, significantly suppressed subcutaneous tumor formation only when treated with gefitinib to nude mice. These results suggest that exogenous expression of CADM1 could provide a unique approach to overcome EGFR-TKI resistance of lung adenocarcinoma caused by MET overexpression. Inversely, loss of CADM1 and cancer cell adhesion could promote EGFR-TKI resistance caused by MET overexpression. Considering that CADM1 expression is lost selectively and clonally in microinvasive lesions of lung adenocarcinoma, disruption of cancer cell adhesion would be involved in generation of cell clones resistant to molecular targeted drugs and resultant heterogeneity in a subset of lung adenocarcinoma. Citation Format: Takehiro Tsuchiya, Hideki Kuwano, Takeshi Ito, Masayoshi Nagata, Taketo Kawai, Yumi Tsuboi, Daisuke Matsubara, Isami Okamoto, Kenji Tamura, Jun Nakajima, Motoi Oba, Yoshinori Murakami. Novel mechanisms of EGFR-TKI resistance and clonal evolution of lung adenocarcinoma by overexpression of a cell adhesion molecule, CADM1 [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-118.