Exosomal miR-136-5p Derived from Anlotinib-Resistant NSCLC Cells Confers Anlotinib Resistance in Non-Small Cell Lung Cancer Through Targeting PPP2R2A

Abstract

Background: Anlotinib resistance is a challenge for advanced non-small cell lung cancer (NSCLC). Understanding the underlying mechanisms against anlotinib resistance is of great importance to improve prognosis and treatment of patients with advanced NSCLC. Methods: RT-qPCR assay was used to assess the level of miR-136-5p in anlotinib-resistant NSCLC cells and exosomes derived from anlotinib-resistant NSCLC cells. In addition, miR-136-5p level in tumor tissues from patients who exhibited a poor response to anlotinib therapy and patients who were therapy naïve or patients who exhibited a positive response to anlotinib therapy was detected by RT-qPCR assay. Results: In this study, we found that high levels of plasma exosomal miR-136-5p is correlated with clinically poor anlotinib response. In addition, anlotinib-resistant NSCLC cells promoted parental NSCLC cell proliferation via transferring functional miR-136-5p from anlotinib-resistant NSCLC cells to parental NSCLC cells via exosomes. Moreover, exosomal miR-136-5p could endow NSCLC cells with anlotinib resistance by targeting PPP2R2A, leading to the activation of Akt pathway. Furthermore, miR-136-5p antagomir packaging into anlotinib-resistant NSCLC cell-derived exosomes functionally restored NSCLC cell anlotinib sensitivity in vitro. Animal studies showed that A549/anlotinib cellderived exosomal miR-136-5p agomir promoted A549 cell anlotinib resistance in vivo. Conclusion: Collectively, these findings indicated that anlotinib-resistant NSCLC cellderived exosomal miR-136-5p confers anlotinib resistance in NSCLC cells by targeting PPP2R2A, indicating miR-136-5p may act as a potential biomarker for anlotinib response in NSCLC.

FGFR2-ERC1: A Subtype of FGFR2 Oncogenic Fusion Variant in Lung Adenocarcinoma and the Response to Anlotinib

“…Furthermore, based on the synergistic effects that anlotinib may have with other treatment options, we may try anlotinib in combination with chemotherapy or immunotherapy. There are currently studies exploring the mechanisms of resistance to anlotinib, for example, miR-136-5p confers resistance to anlotinib in NSCLC cells by targeting PPP2R2A, 39 TFAP2A plays an important role in anlotinib resistance by promoting tumor-induced angiogenesis, 40 CXCL2 is involved in the development of anlotinib resistance in human lung cancer cells. 41 Nevertheless, the mechanism of anlotinib resistance is still unclear, and further exploration is needed to clarify the optimal treatment strategy and drug selection for patients after anlotinib resistance.…”

Exploration of a Novel Circadian miRNA Pair Signature for Predicting Prognosis of Lung Adenocarcinoma

“…While miR-153-3p [ 45 ], and miR-31-5p [ 46 ] were shown to promote the metastasis and invasion of lung cancer cells. In addition, studies have shown that miR-539-3p [ 47 ] and miR -138-5p [ 48 ] enhances chemosensitivity to cisplatin in NSCLC, and miR-136-5p promoted anlotinib resistance in NSCLC [ 49 ]. These studies suggest that these miRNAs play important roles in cancer development.…”

Exosomes: The Role in Tumor Tolerance and the Potential Strategy for Tumor Therapy

“…These exosomes then transferred wild-type EGFR protein to sensitive cells, which induced osimertinib resistance by activating the PI3K/AKT signaling pathways [ 52 ]. Moreover, a report indicated that exosomal miR-136-5p from anlotinib-resistant advanced NSCLC cells induced anlotinib resistance in sensitive NSCLC cells by targeting PPP2R2A [ 53 ]. In addition to the tumor cells, stromal cells in the tumor microenvironment can also deliver drug-resistant miRNAs.…”

“… Exosomes participate in tumor drug resistance. Exosomes participate in tumor drug resistance by directly mediating drug efflux, regulating anti-tumor immune responses, inducing epithelial–mesenchymal transition (EMT) phenotype, and delivering drug resistance [ 39 , 40 , 41 , 42 , 43 , 47 , 48 , 53 , 54 , 55 , 60 , 61 , 66 , 77 , 79 , 80 , 81 , 91 , 95 ]. …”