HER2-positive breast cancer cells resistant to trastuzumab and lapatinib lose reliance upon HER2 and are sensitive to the multitargeted kinase inhibitor sorafenib.

摘要: Trastuzumab has changed the prognosis of HER2 positive breast cancers. Despite this progress, resistance to trastuzumab occurs in most patients. Newer anti-HER2 therapies, like dual tyrosine-kinase inhibitor (TKI) lapatinib, show significant antitumor activity, indicating that can be still exploited as a target after failure. However, since high proportion patients fail respond these alternative strategies, it is possible cell escape from targeting may rely on independent pathways. The knowledge pathways deserve develop new therapies. We characterized two human overexpressing cancer lines resistant and lapatinib (T100 JIMT-1) molecular biological point view. Indeed, we assessed both vitro vivo activity multitarget sorafenib. In lines, previously proposed mechanisms did not explain inhibitors. Notably, silencing by shRNA affect growth our cells, suggesting loss reliance upon HER2. Moreover, identified alterations antiapoptotic proteins Mcl-1 Survivin which are known targets multikinase sorafenib, strongly inhibited T100 JIMT-1 through downregulation Survivin. Similar results were obtained xenografts subcutaneously injected NOD SCID mice. provide preclinical evidence tumor cells efficiently