Dataset Information

De novo lipogenesis represents a therapeutic target in mutant Kras non-small cell lung cancer.

ABSTRACT: Oncogenic Kras mutations are one of the most common alterations in non-small cell lung cancer and are associated with poor response to treatment and reduced survival. Driver oncogenes, such as Kras are now appreciated for their ability to promote tumor growth via up-regulation of anabolic pathways. Therefore, we wanted to identify metabolic vulnerabilities in Kras-mutant lung cancer. Using the Kras LSL-G12D lung cancer model, we show that mutant Kras drives a lipogenic gene-expression program. Stable-isotope analysis reveals that mutant Kras promotes de novo fatty acid synthesis in vitro and in vivo. The importance of fatty acid synthesis in Kras-induced tumorigenesis was evident by decreased tumor formation in Kras LSL-G12D mice after treatment with a fatty acid synthesis inhibitor. Importantly, with gain and loss of function models of mutant Kras, we demonstrate that mutant Kras potentiates the growth inhibitory effects of several fatty acid synthesis inhibitors. These studies highlight the potential to target mutant Kras tumors by taking advantage of the lipogenic phenotype induced by mutant Kras.-Singh, A., Ruiz, C., Bhalla, K., Haley, J. A., Li, Q. K., Acquaah-Mensah, G., Montal, E., Sudini, K. R., Skoulidis, F., Wistuba, I. I., Papadimitrakopoulou, V., Heymach, J. V., Boros, L. G., Gabrielson, E., Carretero, J., Wong, K.-k., Haley, J. D., Biswal, S., Girnun, G. D. De novo lipogenesis represents a therapeutic target in mutant Kras non-small cell lung cancer.

SUBMITTER: Singh A

PROVIDER: S-EPMC6219836 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

De novo lipogenesis represents a therapeutic target in mutant Kras non-small cell lung cancer.

Singh Anju A Ruiz Christian C Bhalla Kavita K Haley John A JA Li Qing Kay QK Acquaah-Mensah George G Montal Emily E Sudini Kuladeep R KR Skoulidis Ferdinandos F Wistuba Ignacio I II Papadimitrakopoulou Vassiliki V Heymach John V JV Boros Laszlo G LG Gabrielson Edward E Carretero Julian J Wong Kwok-Kin KK Haley John D JD Biswal Shyam S Girnun Geoffrey D GD

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20180615

Oncogenic Kras mutations are one of the most common alterations in non-small cell lung cancer and are associated with poor response to treatment and reduced survival. Driver oncogenes, such as Kras are now appreciated for their ability to promote tumor growth via up-regulation of anabolic pathways. Therefore, we wanted to identify metabolic vulnerabilities in Kras-mutant lung cancer. Using the Kras <sup>LSL-G12D</sup> lung cancer model, we show that mutant Kras drives a lipogenic gene-expression ...[more]

PMID: 29906244

Similar Datasets

Project description:BackgroundApproximately 2%-8% of non-small-cell lung cancer (NSCLC) harbors concurrent epidermal growth factor receptor (EGFR) sensitizing mutation and mesenchymal-epithelial transition factor (MET) amplification prior to EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy. This study aimed to investigate the optimal first-line therapeutic options for patients with concurrent EGFR-mutant, MET-overexpressed/amplified advanced NSCLC.MethodsA total of 104 treatment-naïve patients with EGFR-mutant de novo MET-overexpressed advanced NSCLC were identified using immunohistochemistry and stratified to four groups according to treatment regimen: EGFR-TKI monotherapy (n = 48), EGFR-TKI combined with either crizotinib (n = 9) or chemotherapy (n = 12), and chemotherapy (n = 35). A subpopulation of 28 patients was also tested with next-generation sequencing (NGS). Objective response rate (ORR) and progression-free survival (PFS) outcomes were analyzed according to treatment strategies and molecular features.ResultsAll the patients (n = 104) achieved ORR of 36.5% and median PFS (mPFS) of 7.0 months. Baseline clinicopathologic characteristics were similar among the four treatment groups. Compared with chemotherapy, EGFR-TKI monotherapy or EGFR-TKI combination therapy achieved significantly higher ORR (P < 0.001) and longer mPFS (P = 0.003). No ORR or PFS difference was observed between EGFR-TKI monotherapy and combination therapy. In the NGS-identified population (n = 28), patients who received EGFR-TKI plus crizotinib (n = 9) achieved similar ORR (88.9% versus 57.9%, P = 0.195) and mPFS (9.0 versus 8.5 months, hazard ratio 1.10, 95% confidence interval 0.43-2.55, P = 0.45) than those who received EGFR-TKI monotherapy (n = 19), regardless of MET copy number status. Grade 3/4 rashes were significantly more among patients who received EGFR-TKI plus crizotinib (P = 0.026).ConclusionsOur findings provided clinical evidence that patients with concurrent EGFR sensitizing mutation and de novo MET amplification/overexpression could benefit from first-line EGFR-TKI monotherapy.

Dataset Information

De novo lipogenesis represents a therapeutic target in mutant Kras non-small cell lung cancer.

Publications

De novo lipogenesis represents a therapeutic target in mutant Kras non-small cell lung cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure