Wild-type kras allele effects on druggable targets in kras mutant lung adenocarcinomas

Elisa Baldelli, Emna El Gazzah, John Conor Moran, Kimberley A. Hodge, Zarko Manojlovic, Rania Bassiouni, John D. Carpten, Vienna Ludovini, Sara Baglivo, Lucio Crinò, Fortunato Bianconi, Ting Dong, Jeremy Loffredo, Emanuel F. Petricoin, Mariaelena Pierobon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish
Article number1402
Issue number9
StatePublished - Sep 2021
Externally publishedYes


  • Drug target
  • KRAS
  • Non-small cell lung cancer
  • Reverse-phase protein microarray
  • Zygosity


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