An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKi-resistant cells by modulating miR-335 expression

Abstract

Despite current advancements in research and therapeutics, lung cancer remains the leading cause of cancer-related mortality worldwide. This is mainly due to the resistance that patients develop against chemotherapeutic agents over the course of treatment. In the context of non-small cell lung cancers (NSCLC) harboring EGFR oncogenic mutations, augmented levels of AXL and GAS6 have been found to drive resistance to EGFR tyrosine kinase inhibitors such as Erlotinib and Osimertinib in certain tumors with mesenchymal-like features. By studying the ontogeny of AXL-positive cells, we have identified a novel non-genetic mechanism of drug resistance based on cell-state transition. We demonstrate that AXL-positive cells are already present as a sub-population of cancer cells in Erlotinib-naïve tumors and tumor-derived cell lines, and that the expression of AXL is regulated through a stochastic mechanism centered on the epigenetic regulation of miR-335. The existence of a cell-intrinsic program through which AXL-positive/Erlotinib-resistant cells emerge infers the need of treating tumors harboring EGFR-oncogenic mutations upfront with combinatorial treatments targeting both AXL-negative and AXL-positive cancer cells.

EGFR signaling pathway as therapeutic target in human cancers

“…In the same way, overexpression of the RTK AXL (AneXeLekto, uncontrolled), supports EMT-associated resistance to osimertinib, and emergence of tolerant cells via AKT and MAPK [280]. Interestingly, generation of AXL + cells in erlotinib-resistant cells is contingent on methylation of a specific CpG island within the promoter of MEST (MEsoderm Specific Transcript), a gene that contains miR-335 in its second intron [281], defining a potentially novel mechanism coupling epigenetics to ontogeny of resistant cells.…”

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

“… 388 Moreover, miR-335 regulates AXL expression, which leads to EGFR-TKI resistance in NSCLC. 389 In breast cancer cell lines, lapatinib induces Src to activate the NF-κB pathway to upregulate miR-221. High miR-221 leads to death resistance by inhibiting cyclin-dependent kinase inhibitor 1B (p27 kip1 ).…”

Targeting MERTK and AXL in EGFR Mutant Non-Small Cell Lung Cancer

“…MERTK and AXL are frequently aberrantly expressed in NSCLC patient samples, but are absent or expressed at low levels in normal human bronchial epithelial cells [ 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. High levels of AXL have been described in subsets of both treatment-naïve and relapsed NSCLC [ 58 , 59 , 60 ]. Increased AXL expression was associated with increased tumor cell invasiveness and tumor grade and predicted poorer survival in patients with NSCLC [ 56 , 57 , 61 , 62 , 63 , 64 , 65 ].…”

“…High levels of MERTK and/or AXL have also been implicated in drug resistance and radioresistance [ 54 , 55 , 60 , 69 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ]. Increased MERTK or AXL expression in NSCLC correlated with chemotherapy resistance [ 51 , 66 , 70 , 87 , 88 , 89 ].…”

“…Consistent with these findings, high levels of AXL correlated with poor response to initial EGFR TKIs in patients with mt EGFR NSCLC [ 54 , 65 ]. A subpopulation of AXL-positive cancer cells were found in erlotinib-naïve tumors [ 60 ], providing rationale to treat mt EGFR -expressing NSCLCs with AXL and EGFR TKIs combined in order to delay or prevent resistance.…”