Biased signaling by mutant EGFR underlies dependence on PKCα in lung adenocarcinoma
Mojtaba Sadeghi,
Mohamed F. Salama,
Sam B. Chiappone,
Amy Huang,
Andrew E. Resnick,
Manoj Kandpal,
Christopher J. Clarke,
John D. Haley,
Ramana V. Davuluri,
Yusuf A. Hannun
Affiliations
Mojtaba Sadeghi
Department of Biochemistry, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA
Mohamed F. Salama
Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA; Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt
Sam B. Chiappone
Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA
Amy Huang
Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA
Andrew E. Resnick
Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA
Manoj Kandpal
Centre for Clinical and Translational Science, Rockefeller University, New York, NY 10065, USA
Christopher J. Clarke
Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA; Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
John D. Haley
Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA
Ramana V. Davuluri
Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA; Department of Biomedical Informatics, Stony Brook University, Stony Brook, NY 11794, USA
Yusuf A. Hannun
Department of Biochemistry, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA; Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Department of Veterans Affairs, Northport VA Medical Center, Northport, NY 11768, USA; Corresponding author
Summary: Activating mutations in the epidermal growth factor receptor (EGFR) promote ligand-independent signaling; however, the mechanisms involved are poorly defined, and it is unknown whether this generates specific vulnerabilities. We previously observed robust expression of protein kinase Cα (PKCα) in lung adenocarcinoma (LUAD) with mutant EGFR (mEGFR), which, unlike the activation of PKCα, is independent of mEGFR activity. Here, we identify a critical role for PKCα in anchorage-independent growth and survival of lung cancer cells with mEGFR. Mechanistically, signaling pathways initiated by mEGFR show a high preference for ligand-independent phosphorylation on Y992, resulting in biased activation and dependence on phospholipase-Cγ and PKCα. Moreover, through bioinformatic approaches, we find that mEGFR LUAD demonstrates a transcriptomic profile most similar to lung basal cells, which exhibit elevated levels of PKCα, suggesting that mEGFR tumors arise in cell types with high intrinsic levels of PKCα. Taken together, these findings explain the dependence of mEGFR on PKCα.
