Abstract
KRAS mutations are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and in lung adenocarcinomas in particular. Development of therapeutics targeting KRAS has been incredibly challenging, prompting indirect inhibition of downstream targets such as MEK and ERK. Such inhibitors, unfortunately, come with limited clinical efficacy, and therefore the demand for developing novel therapeutic strategies remains an urgent need for these patients. Exploring the influence of wild-type (WT) KRAS on druggable targets can uncover new vulnerabilities for the treatment of KRAS mutant lung adenocarcinomas. Using commercially available KRAS mutant lung adenocarcinoma cell lines, we explored the influence of WT KRAS on signaling networks and druggable targets. Expression and/or activation of 183 signaling proteins, most of which are targets of FDA-approved drugs, were captured by reverse-phase protein microarray (RPPA). Selected findings were validated on a cohort of 23 surgical biospecimens using the RPPA. Kinase-driven signatures associated with the presence of the KRAS WT allele were detected along the MAPK and AKT/mTOR signaling pathway and alterations of cell cycle regulators. FoxM1 emerged as a potential vulnerability of tumors retaining the KRAS WT allele both in cell lines and in the clinical samples. Our findings suggest that loss of WT KRAS impacts on signaling events and druggable targets in KRAS mutant lung adenocarcinomas.
Highlights
Compounds were dissolved in dimethyl sulfoxide (DMSO) (Selumetinib and Siomycin) or phosphate-buffered saline (PBS) (Palbociclib), and cells were treated in a 2-fold serial dilution curve ranging from
In line with previous findings, our study suggests that the presence of the allele allele significantly alters the biology and potential response to treatment for KRAS mutant significantly altersathe biology and potential responsefrom to treatment for KRAS
These mutations with the least percentage of cell lines retaining a WT allele are frequently associated with a worse prognosis [26]
Summary
Small kinase inhibitors able to modulate the activity of aberrantly activated epidermal growth factor receptors (EGFRs) are routinely used as first-line treatment options for EGFR mutant lung adenocarcinomas [5] These targeted molecules have significantly improved response to treatment and survival for these patients. The role of the WT allele on the overall signaling network of these cancer cells is still not fully understood To fill this gap, this study explored activation of signaling transduction networks in KRAS mutant lung adenocarcinomas lacking or retaining the WT copy of the KRAS gene. This study explored activation of signaling transduction networks in KRAS mutant lung adenocarcinomas lacking or retaining the WT copy of the KRAS gene Such approach provided us the unique opportunity to capture the effects of KRAS homo- and heterozygous mutations on druggable signal transduction molecules. Exploring the impact different genotypes can have on cell signaling events will help identify distinct druggable vulnerabilities and potentially advance precision medicine for KRAS mutant lung adenocarcinoma patients
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