Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAFV600 melanoma

Abstract

Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach we demonstrate post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA processing kinase U2AF homology motif kinase 1 (UHMK1) associates with mRNAs encoding metabolism proteins and selectively controls their transport and translation during adaptation to BRAF-targeted therapy. UHMK1 inactivation induces cell death by disrupting therapy induced metabolic reprogramming, and importantly, delays resistance to BRAF and MEK combination therapy in multiple in vivo models. We propose selective mRNA processing and translation by UHMK1 constitutes a mechanism of non-genetic resistance to targeted therapy in melanoma by controlling metabolic plasticity induced by therapy.

UHMK1 promotes lung adenocarcinoma oncogenesis by regulating the PI3K/AKT/mTOR signaling pathway

“… 44 , 45 Interestingly, some studies have indicated that UHMK1 can mediate oxaliplatin, 28 5‐fluorouracil 46 resistance in colorectal cancer, and vemurafenib resistance in melanoma. 22 Our findings might provide insights into UHMK1‐mediated drug resistance in tumors. Apoptosis and autophagy have a profound crosstalk during cancer progression; they may antagonize or assist each other.…”

“…UHMK1 has been implicated as an attractive therapeutic target by exerting its potent oncogenic functions in different ways in many types of cancer. 20 , 21 , 22 , 23 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 40 This motivated us to explore the role and possible mechanism of action of UHMK1 in LUAD. In our study, we identified UHMK1 as significantly overexpressed in LUAD patients, leading to a poor prognosis.…”

“…Research on UHMK1 was initially focused on neurological diseases such as schizophrenia 17 , 18 because of its abundant expression in the nervous system. 19 In the last few years, many researches have revealed the function of UHMK1 in promoting the initiation and progression of different types of cancer, including ovarian cancer, 20 , 21 melanoma, 22 , 23 cervical cancer, 24 liver cancer, 25 , 26 colorectal carcinoma, 27 , 28 pancreatic cancer, 29 , 30 , 31 and gastric cancer. 32 However, no studies have investigated the function and regulatory mechanism of UHMK1 in LUAD.…”

NAD/NAMPT and mTOR Pathways in Melanoma: Drivers of Drug Resistance and Prospective Therapeutic Targets

“…This picture is further complicated by the coexistence within the same tumor of cell populations with different bioenergetic needs and metabolic profiles. Very recent work suggests that post-transcriptional regulation of metabolic genes following BRAF inhibition plays a central role in the adaptation of BRAFV600E melanoma cells via translational reprogramming [ 310 ]. Given the central role of mTORC1 signaling in the regulation of mRNA translation, it is likely that this signaling complex may be involved in this newly discovered adaptive mechanism of resistance to targeted therapy.…”

Dynamical modelling of proliferative-invasive plasticity and IFNγ signaling in melanoma reveals mechanisms of PD-L1 expression heterogeneity

“…Reversible bidirectional switching between a proliferative cell state and a slow-cycling invasive state can promote metastasis in vivo (5). Such proliferative to invasive transition (PIT) and its reverse invasive to proliferative transition (IPT) is often governed by dynamic alterations in the local microenvironment (6), including therapyinduced adaptive cellular changes (7,8). Recent characterization of melanoma cell lines and tumor samples at a single-cell level have indicated that phenotypic heterogeneity in melanoma extends beyond the binary proliferative-invasive paradigm, and cells can dynamically acquire a spectrum of phenotypes (9)(10)(11).…”