RET-mediated autophagy suppression as targetable co-dependence in acute myeloid leukemia

Abstract

Many cases of AML are associated with mutational activation of receptor tyrosine kinases (RTKs) such as FLT3. However, RTK inhibitors have limited clinical efficacy as single agents, indicating that AML is driven by concomitant activation of different signaling molecules. We used a functional genomic approach to identify RET, encoding an RTK, as an essential gene in multiple subtypes of AML, and observed that AML cells show activation of RET signaling via ARTN/GFRA3 and NRTN/GFRA2 ligand/co-receptor complexes. Interrogation of downstream pathways identified mTORC1-mediated suppression of autophagy and subsequent stabilization of leukemogenic drivers such as mutant FLT3 as important RET effectors. Accordingly, genetic or pharmacologic RET inhibition impaired the growth of FLT3-dependent AML cell lines and was accompanied by upregulation of autophagy and FLT3 depletion. RET dependence was also evident in mouse models of AML and primary AML patient samples, and transcriptome and immunohistochemistry analyses identified elevated RET mRNA levels and co-expression of RET and FLT3 proteins in a substantial proportion of AML patients. Our results indicate that RET-mTORC1 signaling promotes AML through autophagy suppression, suggesting that targeting RET or, more broadly, depletion of leukemogenic drivers via autophagy induction provides a therapeutic opportunity in a relevant subset of AML patients.

CXCR4 Inhibition Enhances Efficacy of FLT3 Inhibitors in FLT3-Mutated AML Augmented by Suppressed TGF-β Signaling

“…Activating alterations of the RET kinase are therapeutically actionable oncogenic drivers across a variety of cancers [ 43 ], but the role of RET in hematologic malignancies is less well defined. Recent studies have demonstrated that RET expression may contribute to leukemogenesis in AML models [ 44 , 45 ]. In a model of FLT3-ITD-AML, activation of RET suppressed autophagy, resulting in stabilization of leukemogenic drivers such as mutant FLT3, important RET effectors [ 45 ].…”

The Role of Beclin 1-Dependent Autophagy in Cancer

“…Besides EGFR, HER2, and BCR-ABL, other tyrosine kinases, including RET (involved in acute myeloid leukemia) [78], have been implicated in regulating autophagy, but whether there is any effect in Beclin 1 is not known.…”

Casein kinase 1α inhibits p53 downstream of MDM2‑mediated autophagy and apoptosis in acute myeloid leukemia

“…Jin et al (7) believed that granulocytic AML differentiation relies on noncanonical autophagy pathways and that restoring autophagic activity may be beneficial in differentiation therapies. Several studies have shown that low level of basal autophagy gene expression such as ATG5, ATG7 and LC3 (7,8), and reduced autophagic flux occur in patient-derived AML blasts, and the loss of core autophagy genes results in leukemia initiation and progression in mouse models (9). Pharmacological or genetic inhibition of autophagy leads to impaired leukemic cell viability and increased sensitivity to standard chemotherapy (6,7,10,11).…”