American Association for Cancer Research
10780432ccr123904-sup-supp_figs.pdf (770.89 kB)

Supplementary Figures from Efficacy of BET Bromodomain Inhibition in Kras-Mutant Non–Small Cell Lung Cancer

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journal contribution
posted on 2023-03-31, 17:51 authored by Takeshi Shimamura, Zhao Chen, Margaret Soucheray, Julian Carretero, Eiki Kikuchi, Jeremy H. Tchaicha, Yandi Gao, Katherine A. Cheng, Travis J. Cohoon, Jun Qi, Esra Akbay, Alec C. Kimmelman, Andrew L. Kung, James E. Bradner, Kwok-Kin Wong

Supplementary Figures - PDF file 770K, Supplementary Figure 1. JQ1 treatment induces apoptosis proliferation arrest in a subset of NSCLC cells Supplementary Figure 2. JQ1 treatment promotes a depletion of 57kDa MYC in a time dependent manner in NSCLC cells Supplementary Figure 3. FOSL1 depletion is induced by JQ1 treatment regardless of the status of LKB1 Supplementary Figure 4. JQ1 treatment in mutant kras mouse induce apoptosis



Purpose: Amplification of MYC is one of the most common genetic alterations in lung cancer, contributing to a myriad of phenotypes associated with growth, invasion, and drug resistance. Murine genetics has established both the centrality of somatic alterations of Kras in lung cancer, as well as the dependency of mutant Kras tumors on MYC function. Unfortunately, drug-like small-molecule inhibitors of KRAS and MYC have yet to be realized. The recent discovery, in hematologic malignancies, that bromodomain and extra-terminal (BET) bromodomain inhibition impairs MYC expression and MYC transcriptional function established the rationale of targeting KRAS-driven non–small cell lung cancer (NSCLC) with BET inhibition.Experimental Design: We performed functional assays to evaluate the effects of JQ1 in genetically defined NSCLC cell lines harboring KRAS and/or LKB1 mutations. Furthermore, we evaluated JQ1 in transgenic mouse lung cancer models expressing mutant kras or concurrent mutant kras and lkb1. Effects of bromodomain inhibition on transcriptional pathways were explored and validated by expression analysis.Results: Although JQ1 is broadly active in NSCLC cells, activity of JQ1 in mutant KRAS NSCLC is abrogated by concurrent alteration or genetic knockdown of LKB1. In sensitive NSCLC models, JQ1 treatment results in the coordinate downregulation of the MYC-dependent transcriptional program. We found that JQ1 treatment produces significant tumor regression in mutant kras mice. As predicted, tumors from mutant kras and lkb1 mice did not respond to JQ1.Conclusion: Bromodomain inhibition comprises a promising therapeutic strategy for KRAS-mutant NSCLC with wild-type LKB1, via inhibition of MYC function. Clinical studies of BET bromodomain inhibitors in aggressive NSCLC will be actively pursued. Clin Cancer Res; 19(22); 6183–92. ©2013 AACR.

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