Study on the mechanism of tyrosine kinase inhibitor resistance by the FAM167A/DSG1 signaling axis in chronic myeloid leukemia patients

Abstract

Drug resistance is one of the most difficult challenges in cancer therapies. Chronic myeloid leukemia (CML) is a representative cancer in which targeted drugs can significantly increase patient survival, yet drug resistance prevents a complete cure, causing progression and recurrence of the cancer. For treatment of this resistance, a number of next-generation tyrosine kinase inhibitors (TKIs) have been developed. However, BCR-ABL-independent resistance that cannot be overcome with TKI monotherapy remains a barrier to the curative treatment of CML patients, and the mechanism underlying BCR-ABL-independent TKI resistance requires further investigation. Here, I show that the previously uncharacterized protein FAM167A has an essential role in BCR-ABL-independent TKI resistance as an inducer of the noncanonical NF-kB pathway. Mechanistic analyses revealed that FAM167A activates the noncanonical NF-kB pathway by binding to desmoglein-1 (DSG1) and regulating NF-kB-inducing kinase (NIK) ubiquitination. FAM167A neutralization reduces noncanonical NF-kB activity and restores sensitivity to TKIs in vitro and in a mouse tumor model in vivo. Furthermore, FAM167A and surface DSG1 levels were found to be highly upregulated in CD34+ CML cells from patients with BCR-ABL-independent TKI resistance. These findings show that FAM167A acts as a novel essential factor for BCR-ABL-independent TKI resistance in CML through noncanonical NF-kB pathway activation.