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

Abstract

SUMMARY 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 potential targeted treatment approach for MYC-driven SCLC.

The Expanding World of N-MYC–Driven Tumors

“…Molecular analyses of these models showed that L-MYC activates eIF2 and mTOR signaling pathways, which are both involved in ribosomal biogenesis and protein production and which is consistent with a comparison to N-MYC target genes (101). Although there are no studies that have addressed the ability of N-MYC to act as a driver of SCLC, recent data from a GEMM study suggests that, as in prostate cancer, C-MYC overexpression does not drive a neuroendocrine phenotype in lung cancer (125). In this study, mice were engineered to overexpress C-MYC in the context of Rb1/Trp53 double knockout (RPM) in lung neuroendocrine cells (using the neuroendocrine calcitonin gene-related peptide promoter).…”

“…This approach also extends beyond N-MYC (e.g., C-MYC-driven SCLC models; refs. 105,125,165). On the basis of the structural data (146), it may now be possible to design new strategies that would avoid the toxicity problems of the current Aurora-A inhibitors to inhibit the protein-protein interaction of the Aurora-A/N-MYC complex directly by targeting the interface without disrupting the cellcycle function of Aurora-A.…”

Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models

“…Interestingly, these features are reminiscent of a so-called "variant" subtype of human SCLC (as opposed to a "classic" neuroendocrine phenotype), which was initially identified in SCLC cell lines (62)(63)(64)(65). Importantly, this variant subtype of SCLC with high levels of c-Myc may be particularly sensitive to inhibitors of Aurora kinase (17,66), providing an elegant demonstration that genotype can determine therapeutic response in SCLC. MYC expression may also be a marker of sensitivity to CHK1 inhibitors (24).…”

“…Ectopic expression o f c -M y c i n p r e n e o p l a s t i c , R b / p 5 3 / p 1 3 0 m u t a n t neuroendocrine lung epithelial cells is sufficient to transform these cells (61). High levels of c-Myc (in its more stable form Myc T58A ) rapidly transform Rb/p53 mutant neuroendocrine lung epithelial cells (17). These Rb/p53/Myc mutant tumors express lower levels of neuroendocrine markers compared to classical SCLC GEMMs and express low levels of Ascl1 and high levels of NeuroD1 (17).…”

“…High levels of c-Myc (in its more stable form Myc T58A ) rapidly transform Rb/p53 mutant neuroendocrine lung epithelial cells (17). These Rb/p53/Myc mutant tumors express lower levels of neuroendocrine markers compared to classical SCLC GEMMs and express low levels of Ascl1 and high levels of NeuroD1 (17). Interestingly, these features are reminiscent of a so-called "variant" subtype of human SCLC (as opposed to a "classic" neuroendocrine phenotype), which was initially identified in SCLC cell lines (62)(63)(64)(65).…”