Integrated Analysis of Transcriptomes of Cancer Cell Lines and Patient Samples Reveals STK11/LKB1–Driven Regulation of cAMP Phosphodiesterase-4D

Abstract

The recent proliferation of data on large collections of well-characterized cancer cell lines linked to therapeutic drug responses has made it possible to identify lineage-and mutation-specific transcriptional markers that can help optimize implementation of anticancer agents. Here, we leverage these resources to systematically investigate the presence of mutation-specific transcription markers in a wide variety of cancer lineages and genotypes. Sensitivity and specificity of potential transcriptional biomarkers were simultaneously analyzed in 19 cell lineages grouped into 228 categories based on the mutational genotypes of 12 cancer-related genes. Among a total of 1,455 category-specific expression patterns, the expression of cAMP phosphodiesterase-4D (PDE4D) with 11 isoforms, one of the PDE4(A-D) subfamilies, was predicted to be regulated by a mutant form of serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) present in lung cancer. STK11/ LKB1 is the primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK). Subsequently, we found that the knockdown of PDE4D gene expression inhibited proliferation of STK11-mutated lung cancer lines. Furthermore, challenge with a panel of PDE4-specific inhibitors was shown to selectively reduce the growth of STK11-mutated lung cancer lines. Thus, we show that multidimensional analysis of a well-characterized large-scale panel of cancer cell lines provides unprecedented opportunities for the identification of unexpected oncogenic mechanisms and mutation-specific drug targets. Mol Cancer Ther; 13(10); 2463-73. Ó2014 AACR.

Cardiac glycosides display selective efficacy for STK11 mutant lung cancer

“…The tumor suppressor STK11 is inactivated in 30% of lung cancer cases (∼20% of lung adenocarcinoma (LUAD) cases) 1 . Despite the importance of STK11 in lung cancer 1 2 3 and the observation that therapeutic approaches for other types of cancer harboring genetic alterations have impacted patient care ( Supplementary Table S1 ), targeted therapeutic approaches have not yet been implemented for lung cancer harboring STK11 mutations, a loss-of-function aberration. It remains challenging to identify effective targets with a clear mechanistic explanation for the concerted role of a target and a loss-of-function mutation.…”

Glucose starvation induces mutation and lineage-dependent adaptive responses in a large collection of cancer cell lines

“…In this study, we analyzed adaptive responses to glucose deprivation across tumor lineage and mutational genotypes. Combined categorization of a large cell line panel by lineage and mutation criteria has been successfully used to find new molecular signatures from different omics datasets ( 19 , 20 ).…”

Epac1, PDE4, and PKC protein expression and their association with AKAP95, Cx43, and cyclinD2/E1 in breast cancer tissues

“…PDE4 is a member of the cAMP-specific phosphodiesterase family and plays an important role in regulating intracellular cAMP concentration and its downstream signaling. The decreased expression of the PDE4D gene inhibited the proliferation of lung cancer cells with serine/ threonine kinase 11 (STK11) mutations, 11 while as a tumor promoting factor, PDE4D played an important role in cancer cell progression. 12 We did not observe any difference in the positive rate of PDE4 protein expression between breast cancer and para-carcinoma tissues.…”