Genetic requirement forMycland efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer

Abstract

Small cell lung cancer (SCLC) is a devastating neuroendocrine carcinoma. MYCL (L-Myc) is frequently amplified in human SCLC, but its roles in SCLC progression are poorly understood. We isolated preneoplastic neuroendocrine cells from a mouse model of SCLC and found that ectopic expression of L-Myc, c-Myc, or N-Myc conferred tumorforming capacity. We focused on L-Myc, which promoted pre-rRNA synthesis and transcriptional programs associated with ribosomal biogenesis. Deletion of Mycl in two genetically engineered models of SCLC resulted in strong suppression of SCLC. The high degree of suppression suggested that L-Myc may constitute a therapeutic target for a broad subset of SCLC. We then used an RNA polymerase I inhibitor to target rRNA synthesis in an autochthonous Rb/p53-deleted mouse SCLC model and found significant tumor inhibition. These data reveal that activation of RNA polymerase I by L-Myc and other MYC family proteins provides an axis of vulnerability for this recalcitrant cancer.

FGFR1 is critical for Rbl2 loss-driven tumor development and requires PLCG1 activation for continued growth of small cell lung cancer

“…FGFR1, despite its recurrent amplification in SCLC patient tumors, is not amplified in the GEMMs of SCLC [3,20]. Instead, Affymetrix gene-chip revealed a significant increase in Fgfr1 transcript levels in murine SCLC cells relative to preSCs [19]. RT-qPCR validated the increased level of Fgfr1 transcript, and immunoblot confirmed the increase at the protein level in murine SCLC cells and primary tumors relative to preSCs and normal lung ( Fig.…”

“…To characterize FGFR1 in SCLC development, we utilized genetically engineered mouse models (GEMM) in which adenoviral Cre (Ad-Cre)-driven conditional deletion of both Rb1 and Trp53, mimicking the same set of alterations found in more than 90% of SCLC patient tumors, recapitulates most of the pathophysiological features of the human disease [15]. GEMMs facilitated determining the roles for SCLC recurrent alterations, including MYCL1, MYC, RBL2, and PTEN [6,[16][17][18][19][20][21][22][23]. In this study, we tested a model of FGFR1 amplification in precancerous neuroendocrine cells (preSCs) that transform into SCLC upon activation of oncogenic drivers [19,24].…”

“…GEMMs facilitated determining the roles for SCLC recurrent alterations, including MYCL1, MYC, RBL2, and PTEN [6,[16][17][18][19][20][21][22][23]. In this study, we tested a model of FGFR1 amplification in precancerous neuroendocrine cells (preSCs) that transform into SCLC upon activation of oncogenic drivers [19,24]. We tested the requirement of FGFR1 for SCLC development using genetically engineered mouse models.…”

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

“…Another key future step will be the development of better models to investigate how specific genetic events may lead to the development of distinct subtypes of SCLC tumors. One promising approach will be to use pre-neoplastic SCLC and test specific oncogenes or tumor suppressors (61); another approach may be to develop faster GEMMs using CRISPR/Cas9 approaches in vivo to manipulate specific genes and specific populations of cells. Faster modeling approaches may become critical as recent studies point to a number of new targets and possible biomarkers predictive of sensitivity or resistance to new therapeutics [e.g., AXL expression and resistance to Wee1 inhibition (77), p53 point mutations and chemotherapy response (78), or DNA methylation as a biomarker for the effects of LSD1 inhibitors (79)].…”

“…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).…”