SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors

Abstract

The cyclin-dependent kinase 4/6 (CDK4/6) kinase is dysregulated in melanoma, highlighting it as a potential therapeutic target. CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern, and the molecular mechanisms of such resistance remain undefined. We demonstrate that reactivation of mammalian target of rapamycin 1 (mTORC1) signaling through increased expression of the amino acid transporter, solute carrier family 36 member 1 (SLC36A1), drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms: (i) Rb loss, which drives SLC36A1 via reduced suppression of E2f; (ii) fragile X mental retardation syndrome–associated protein 1 overexpression, which promotes SLC36A1 translation and subsequently mTORC1. Last, we demonstrate that a combination of a CDK4/6 inhibitor with an mTORC1 inhibitor has increased therapeutic efficacy in vivo, providing an important avenue for improved therapeutic intervention in aggressive melanoma.

Regulation of mTORC1 by Upstream Stimuli

“…SLC3A2/SLC7A5, in addition to SLC1A5, have also been demonstrated to promote mTORC1 activity through Gln regulation [ 126 ]. SLC36A1 (PAT1), which transports Ala, Gly and Pro, was shown to positively regulate mTORC1 activation [ 127 , 128 ]. This transporter was found to drive mTORC1 signaling and contribute to cyclin dependent kinase 4/6 (CDK4/6) inhibitor resistance in melanoma.…”

Systemic muscle wasting and coordinated tumour response drive tumourigenesis

“…Tor-S6K signalling is implicated downstream of SLC36 transporters 29,30 . Expression of a dominant-negative isoform of Tor in Ras/Src-activated cells (ras1 G12V ,Tor TED ;csk −/− ) suppressed tumour growth in HSD (Fig.…”

Fbxl8 suppresses lymphoma growth and hematopoietic transformation through degradation of cyclin D3

“…Consistently, we found that cyclin D3 expression is negatively correlated with Fbxl8 expression in human lymphomas and low level of Fbxl8 correlates poor overall survival for lymphoma patients, supporting our conclusion that Fbxl8-cyclin D3 axis has a critical role in regulating cell cycle and tumorigenesis. CDK4/6 inhibitors are being used for many clinical trials and the efficacy has been assessed in many types of cancers where cyclin D1 is overexpressed [24,[29][30][31]. Our data demonstrate that cyclin D3T283A accumulates in the nucleus and promotes oncogene-induced tumorigenesis in hematopoietic cells, reflecting increased CDK activity.…”

“…CDK4/6 inhibitors are being used for many clinical trials and the efficacy has been assessed in many types of cancers where cyclin D1 is overexpressed [ 24 , 29 – 31 ]. Our data demonstrate that cyclin D3T283A accumulates in the nucleus and promotes oncogene-induced tumorigenesis in hematopoietic cells, reflecting increased CDK activity.…”