In:
Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 17_Supplement ( 2018-09-01), p. IA27-IA27
Abstract:
Small cell lung cancer (SCLC) has largely been treated in the clinic as a homogeneous disease for the last 40 years. However, it is become increasingly appreciated that SCLC exhibits both intra- and intertumoral heterogeneity. Genetic loss of the tumor suppressors RB1 and TP53 is nearly universal in SCLC, while amplifications in MYC family members including C-, L-, and N-MYC are mutually exclusive. Using genetically engineered mouse models (GEMMs), we show that MycT58A 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 low ASCL1 and high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. The MYC-driven subset of SCLC is also low for other clinically relevant biomarkers such as TTF1/NKX2.1 and DLL3. 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 findings are consistent with the results of recent clinical trials in patients with relapsed SCLC who received paclitaxel with or without the AURKA inhibitor alisertib. Furthermore, recent preclinical studies demonstrate that the MYC-driven subset of SCLC is preferentially sensitive to CHK1 inhibition and other metabolic targets compared to MYCL-driven SCLC. These data identify molecular features for patient stratification and uncover potential targeted treatment approaches for MYC-driven SCLC. Citation Format: Gurkan Mollaoglu, Matthew R. Guthrie, Stefanie Bohm, Johannes Bragelmann, Milind D. Chalishazar, Abbie S. Ireland, Fang Huang, Zeping Hu, Robert J. Cardnell, Triparna Sen, Jason Gertz, Jane E. Johnson, Adi F. Gazdar, Lauren A. Byers, Ralph J. DeBerardinis, Robert J. Wechsler-Reya, Martin Sos, Trudy G. Oliver. MYC drives molecular and therapeutically distinct subtype of SCLC [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA27.
Type of Medium:
Online Resource
ISSN:
1078-0432
,
1557-3265
DOI:
10.1158/1557-3265.AACRIASLC18-IA27
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
detail.hit.zdb_id:
1225457-5
detail.hit.zdb_id:
2036787-9
