Targeting the MYC pathway for therapeutic intervention of cancer metabolism and apoptosis

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Title: Targeting the MYC pathway for therapeutic intervention of cancer metabolism and apoptosis
Author: Haikala, Heidi
Contributor: University of Helsinki, Faculty of Medicine, Research Programs Unit
Date: 2017-06-09
Thesis level: Doctoral dissertation (article-based)
Abstract: MYC is a transcription factor and a proto-oncogene, which is overexpressed in almost 50% of all breast cancers. Cell cycle promoting oncogenic MYC supports the altered energetic needs of continuously proliferating cancer cells, since there is an immense requirement for nucleic acids, proteins, and lipids to support the cell division. MYC supports the metabolic switch by enhancing the main nutrient (glucose and glutamine) uptake, increasing glycolysis and glutamine utilization, as well as by instructing the normally ATP generating citric acid cycle to serve biosynthetic growth promoting reactions. In this study we found that the metabolic changes induced by MYC lead to decreased production of ATP and the consequent activation of a key cellular energy sensor protein AMP-activated kinase (AMPK). AMPK is a metabolic guardian, which instructs cells to perform catabolic reactions to restore the ATP levels. However, persistent AMPK activity directs MYC-transformed cells towards apoptotic cell death. We found that MYC-activated AMPK phosphorylated the tumor suppressor protein p53, which accumulated on the mitochondrial surface. In the mitochondria, p53 primed the cell death promoting protein BAK for apoptotic cell death induction, thus connecting MYC-driven metabolic transformation to apoptotic sensitivity. In addition, we discovered a novel synthetic lethal and potentially druggable interaction between MYC activation and inhibition of a small GTPase RhoA. We found that RhoA assists MYC to upregulate glutamine metabolism, which highlights the relevance of metabolism as a sweet spot for targeting oncogenic MYC. Furthermore, we found that supraphysiological, highly expressed MYC is globally repressing the transcriptional targets of serum response factor (SRF), a RhoA downstream target, thus exposing new pathways needed for cancer cell survival. In addition, the same study contributed to a finding that supraphysiological MYC represses a set of genes related to luminal identity of breast epithelial cells, which possibly affects the cell differentiation and apoptotic sensitivity in vivo. The described mechanisms suggest a possible answer to the old paradox why cancerous MYC expression levels, but not physiological MYC, sensitize cells to apoptosis. Finally we studied how the altered metabolism-derived sensitivity to apoptosis could be exploited as a potential therapeutic strategy to kill MYC expressing cancer cells. In a rationalized drug combination screen, we found that the pharmacological superactivation of AMPK is able to potentiate the anticancer activity of apoptosis targeting therapies, which usually do not show great efficacy in solid tumors as single agents. The described combination proved substantial efficacy against highly MYC expressing breast cancer models in vitro, in vivo and in ex vivo. Thus, we describe the first pharmacological MYC apoptosis activation strategy that could be easily translated to the benefit of breast cancer patients, and currently clinical trials to test the combination are under consideration. In addition to the described scientific findings, the ex vivo and in vivo preclinical research models of breast cancers developed during this study are likely to serve breast cancer research community by providing more predictive and more translationally relevant platforms for studies of breast cancer biology and drug discovery.Syöpäsolut joutuvat muuttamaan aineenvaihduntaansa tukeakseen solujen jatkuvaa jakaantumista. Väitöskirjatyön tavoitteena on ollut löytää uusia täsmähoitoja MYC syöpägeenin aiheuttamiin aineenvaihdunnan muutoksiin rintasyövissä. MYC on yksi yleisimmistä syöpägeeneistä; se on yli-ilmentynyt lähes 50% rintasyövistä. MYC saa solut jakaantumaan ja vauhdittaa niiden aineenvaihduntaa sekä energian saantia, mutta samalla herkistää solut itsemurhalle, eli ohjelmoidulle solukuolemalle (apoptoosille). Väitöskirjatyössä näytetään, että juuri MYC:in aiheuttamat aineenvaihdunnan muutokset herkistävät solut kuolemaan, ja että tätä herkkyyttä voidaan käyttää terapeuttisesti syöpäsoluja vastaan apoptoosiin ja aineenvaihduntaan kohdentuvia lääkeaineita yhdistellen. Uutta yhdistelmähoitoa voitaisiin mahdollisesti käyttää esimerkiksi pitkälle levinneiden triplanegatiivisten rintasyöpien hoitoon, joissa MYC on usein aktiivinen. Aineenvaihdunnan muutokset ovat hyvin spesifejä juuri syöpäsoluille, joten siihen kohdistuvilla täsmähoidoilla pystyttäisiin todennäköisesti välttämään epätoivotut sivuvaikutukset normaaleihin soluihin. Lisäksi tutkimuksessa on pystytetty uusia syöpätutkimusmalleja, joissa potilaan omia soluja viljellään kolmiulotteisissa geeliviljelmissä. Uutta tutkimusmallia voidaan käyttää rintasyövän täsmälääkkeiden ja lääkeyhdistelmien tutkimukseen, sekä tulevaisuudessa toivottavasti myös lääkeaineiden tehon ennustamiseen potilaissa.
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