Trop2 binding IGF2R induces gefitinib resistance in NSCLC by remodeling the tumor microenvironment

Xia Sun; Lizhou Jia; Tengqi Wang; Yulian Zhang; Wei Zhao; Xiangcheng Wang; Hao Chen

doi:10.7150/jca.57711

Trop2 binding IGF2R induces gefitinib resistance in NSCLC by remodeling the tumor microenvironment

J Cancer. 2021 Jul 3;12(17):5310-5319. doi: 10.7150/jca.57711. eCollection 2021.

Authors

Xia Sun¹, Lizhou Jia^{2

3}, Tengqi Wang³, Yulian Zhang¹, Wei Zhao⁴, Xiangcheng Wang^{5

6}, Hao Chen^{2

7}

Affiliations

¹ Emergency Center, Bayannur Hospital, Bayannur, Inner Mongolia, 015000, China.
² Department of Pathology, Wannan Medical College, Wuhu, Anhui, 241002, China.
³ Cancer Center, Bayannur Hospital, Inner Mongolia, 015000, China.
⁴ Department of Pathology, Nanjing First Hospital, Nanjing, Jiangsu, 211166, China.
⁵ Department of nuclear medicine, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010050, China.
⁶ Key Laboratory of Inner Mongolia Autonomous Region Molecular Imaging, Inner Mongolia Medical University, Hohhot, 010050, China.
⁷ Faculty of medical science, Jinan University, Guangzhou, Guangdong, 510632, China.

Abstract

Gefitinib has shown good efficacy in treating recurrent or advanced non-small cell lung cancer (NSCLC), but the drug resistance remains a clinical challenge in medical oncology. In addition, the complex interaction between tumor cells and heterogeneous stromal cells in the adjacent tumor microenvironment (TME) is also an important contributor to drug resistance. So, it is very necessary to detect the related target genes before and after gefitinib treatment dynamically. In this study, the relationship between Trop2 and gefitinib resistance in NSCLC was investigated, and the underlying mechanism was explored. Results showed that Trop2 was associated with EGFR gene mutation and drug resistance in clinical tissues. Trop2 was confirmed to induce gefitinib resistance in NSCLC, and Trop2 binding IGF2R promoted the IGF2-IGF1R-Akt axis to enhance gefitinib resistance and remodeling the TME in NSCLC. Notably, silencing of Trop2 in cancer cells combined with IGF1R inhibitor significantly decreased the proliferation of tumor cells and reshaped the NSCLC TME in vivo and in vitro, including the recruitment of macrophages. These findings deepened the understanding of the function of Trop2 and the involved mechanisms of gefitinib resistance, and may provide new molecular targets for NSCLC with gefitinib resistance.

Keywords: IGF2R; NSCLC; TME; Trop2; drug resistance; gefitinib.