MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically.
journal contributionposted on 2020-10-21, 13:32 authored by Enkhtsetseg Munkhbaatar, Michelle Dietzen, Deepti Agrawal, Martina Anton, Moritz Jesinghaus, Melanie Boxberg, Nicole Pfarr, Pidassa Bidola, Sebastian Uhrig, Ulrike Höckendorf, Anna-Lena Meinhardt, Adam Wahida, Irina Heid, Rickmer Braren, Ritu Mishra, Arne Warth, Thomas Muley, Patrina SP Poh, Xin Wang, Stefan Fröhling, Katja Steiger, Julia Slotta-Huspenina, Martijn van Griensven, Franz Pfeiffer, Sebastian Lange, Roland Rad, Magda Spella, Georgios T Stathopoulos, Jürgen Ruland, Florian Bassermann, Wilko Weichert, Andreas Strasser, Caterina Branca, Mathias Heikenwalder, Charles Swanton, Nicholas McGranahan, Philipp J Jost
Evasion of programmed cell death represents a critical form of oncogene addiction in cancer cells. Understanding the molecular mechanisms underpinning cancer cell survival despite the oncogenic stress could provide a molecular basis for potential therapeutic interventions. Here we explore the role of pro-survival genes in cancer cell integrity during clonal evolution in non-small cell lung cancer (NSCLC). We identify gains of MCL-1 at high frequency in multiple independent NSCLC cohorts, occurring both clonally and subclonally. Clonal loss of functional TP53 is significantly associated with subclonal gains of MCL-1. In mice, tumour progression is delayed upon pharmacologic or genetic inhibition of MCL-1. These findings reveal that MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically.
Crick (Grant ID: 10169, Grant title: Swanton FC001169)
AnimalsAntineoplastic AgentsApoptosisCarcinoma, Non-Small-Cell LungCell Line, TumorCell SurvivalClonal EvolutionDNA Copy Number VariationsDatasets as TopicDisease Models, AnimalDisease ProgressionHumansLungLung NeoplasmsMiceMice, TransgenicMutationMyeloid Cell Leukemia Sequence 1 ProteinPrimary Cell CultureProspective StudiesProto-Oncogene Proteins p21(ras)PyrimidinesRNA-SeqRetrospective StudiesSpheroids, CellularThiophenesTumor BurdenTumor Suppressor Protein p53X-Ray MicrotomographySwanton FC001169