MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low “variant” subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which combined with chemotherapy strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a novel targeted treatment approach for MYC-driven SCLC.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 4 Publications

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Dataset ID	Description	Technology	Samples
EGAD00001003099	RNAseq data set (Mollaoglu et al., MYC drives progression of small cell lung cancer to a variant neuroendocrine subtype with vulnerability to Aurora kinase inhibition) RNA isolation from primary tumors and healthy lungs was performed using RNeasy Mini Kit (Qiagen) with the standard protocol. RNA was subjected to library construction with the Illumina TruSeq Stranded mRNA Sample Preparation Kit (cat# RS-122-2101, RS-122-2102) according to manufacturer’s protocol. Chemically denatured sequencing libraries (25 pM) are applied to an Illumina HiSeq v4 single read flow cell using an Illumina cBot. Hybridized molecules were clonally amplified and annealed to sequencing primers with reagents from an Illumina HiSeq SR Cluster Kit v4-cBot (GD-401-4001). Following transfer of the flowcell to an Illumina HiSeq 2500 instrument (HCSv2.2.38 and RTA v1.18.61), a 50 cycle single-read sequence run was performed using HiSeq SBS Kit v4 sequencing reagents (FC-401-4002).	Illumina HiSeq 2000	14

Publications	Citations
MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. Mollaoglu G, Guthrie MR, Böhm S, Brägelmann J, Can I, Ballieu PM, Marx A, George J, Heinen C, Chalishazar MD, Cheng H, Ireland AS, Denning KE, Mukhopadhyay A, Vahrenkamp JM, Berrett KC, Mosbruger TL, Wang J, Kohan JL, Salama ME, Witt BL, Peifer M, Thomas RK, Gertz J, Johnson JE, Gazdar AF, Wechsler-Reya RJ, Sos ML, Oliver TG. Cancer Cell 31: 2017 270-285	311
MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer. Dammert MA, Brägelmann J, Olsen RR, Böhm S, Monhasery N, Whitney CP, Chalishazar MD, Tumbrink HL, Guthrie MR, Klein S, Ireland AS, Ryan J, Schmitt A, Marx A, Ozretić L, Castiglione R, Lorenz C, Jachimowicz RD, Wolf E, Thomas RK, Poirier JT, Büttner R, Sen T, Byers LA, Reinhardt HC, Letai A, Oliver TG, Sos ML. Nat Commun 10: 2019 3485	40
Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes. Bebber CM, Thomas ES, Stroh J, Chen Z, Androulidaki A, Schmitt A, Höhne MN, Stüker L, de Pádua Alves C, Khonsari A, Dammert MA, Parmaksiz F, Tumbrink HL, Beleggia F, Sos ML, Riemer J, George J, Brodesser S, Thomas RK, Reinhardt HC, von Karstedt S. Nat Commun 12: 2021 2048	62
Non-canonical integrin signaling activates EGFR and RAS-MAPK-ERK signaling in small cell lung cancer. Rubio K, Romero-Olmedo AJ, Sarvari P, Swaminathan G, Ranvir VP, Rogel-Ayala DG, Cordero J, Günther S, Mehta A, Bassaly B, Braubach P, Wygrecka M, Gattenlöhner S, Tresch A, Braun T, Dobreva G, Rivera MN, Singh I, Graumann J, Barreto G. Theranostics 13: 2023 2384-2407	7