Editors' ChoiceCancer

Making cancer cells dependent on EGFR

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Science Signaling  29 Mar 2016:
Vol. 9, Issue 421, pp. ec72
DOI: 10.1126/scisignal.aaf7589

Some breast cancers have increased abundance of epidermal growth factor receptor (EGFR) family members, such as EGFR and HER2. Antibodies that block EGFRs have initial success in patients, but tumors inevitably develop resistance and recur. Two studies now show how resistance can be overcome by inhibiting enzymes that suppress EGFR family abundance or activity. Using transgenic mice, Goel et al. (also see Malumbres) found that recurrent mammary tumors that were resistant to a HER2-blocking antibody had increased abundance of cyclin-D1 and cyclin-dependent kinase 4 (CDK4). The expression of the gene encoding cyclin-D1 in patient tumor tissues positively correlated with clinical resistance to EGFR inhibitors. Tumor cells were sensitive to knockdown or pharmacological inhibition of cyclin-D1 or CDK4 and CDK6 (CDK4/6), respectively. Inhibiting CDK4/6 not only suppressed tumor growth in mice but resensitized the tumors to EGFR inhibitors when combined. When in complex with cyclin-D1, CDK4 phosphorylates and inhibits tuberous sclerosis 2 (TSC2), a protein that inhibits the kinase complex mTORC1; mTORC1 promotes negative feedback regulation of EGFR signaling. Thus, by relieving TSC2, CDK4/6 inhibition suppressed negative feedback and enabled increased activity of EGFR family members, thereby making cells more sensitive to EGFR inhibitors. This week in Science Signaling, Gao et al. uncovered a target in lung cancer that similarly resensitizes tumors to EGFR inhibitors. EGFR-mutant non–small cell lung cancer (NSCLC) cells that were resistant to the EGFR inhibitor erlotinib had increased abundance and activity of the kinase JAK2. Xenografted tumors in mice were sensitive to combined therapy of erlotinib plus a JAK2 inhibitor. JAK2 promoted the formation of a complex between EGFR and the protein SOCS5, which promotes the internalization and ubiquitin-mediated degradation of receptors. Thus, by decreasing this interaction, JAK2 inhibitors increased the abundance of EGFR on the tumor cell surface, the activity of which could then be blocked by EGFR inhibitors. The two studies reveal new combination therapies that, counterintuitively, relieve negative regulation of EGFRs to resensitize tumors to EGFR inhibitors.

S. Goel, Q. Wang, A. C. Watt, S. M. Tolaney, D. A. Dillon, W. Li, S. Ramm, A. C. Palmer, H. Yuzugullu, V. Varadan, D. Tuck, L. N. Harris, K.-K. Wong, X. S. Liu, P. Sicinski, E. P. Winer, I. E. Krop, J. J. Zhao, Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell 29, 255–269 (2016). [PubMed]

M. Malumbres, CDK4/6 inhibitors resTORe therapeutic sensitivity in HER2+ breast cancer. Cancer Cell 29, 243–244 (2016). [PubMed]

S. P. Gao, Q. Chang, N. Mao, L. A. Daly, R. Vogel, T. Chan, S. H. Liu, E. Bournazou, E. Schori, H. Zhang, M. Red Brewer, W. Pao, L. Morris, M. Ladanyi, M. Arcila, K. Manova-Todorova, E. de Stanchina, L. Norton , R. L. Levine, G. Altan-Bonnet, D, Solit, M. Zinda, D. Huszar, D. Lyden, J. F. Bromberg, JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors. Sci. Signal. 9, ra33 (2016). [Abstract]