Abstract
CUDC-101 is a novel, small-molecule, anticancer agent targeting histone deacetylase (HDAC), EGF receptor (EGFR), and HER2. It is currently in phase I clinical development in patients with solid tumors. Previously, we reported that CUDC-101 has potent antiproliferative and proapoptotic activity in cultured tumor cells and in vivo xenograft models. We now show that cancer cells that have acquired resistance to single-target EGFR inhibitors through upregulation of AXL or loss of E-cadherin remain sensitive to CUDC-101, which inhibits MET- and AXL-mediated signaling, restores E-cadherin expression, and reduces cell migration. CUDC-101 also efficiently inhibited the proliferation of MET-overexpressing non-small cell lung cancer and gastric cancer cell lines and inhibited the migration and invasion of invasive tumor cells. Taken together, these results suggest that coupling HDAC and HER2 inhibitory activities to an EGFR inhibitor may potentially be effective in overcoming drug resistance and preventing cancer cell migration.
Highlights
During the past several years, 4 EGF receptor (EGFR) inhibitors, gefitinib, erlotinib, cetuximab, and panitumumab, have been approved and have become standard-ofcare for use in patients with cancer
We showed the antidrug resistance and antimetastatic activities of CUDC-101, a multitarget histone deacetylase (HDAC), EGFR, and HER2 inhibitor
Our results suggest that EGFR, HER2, and HDAC inhibition synergizes to overcome EGFR inhibitor resistance
Summary
During the past several years, 4 EGF receptor (EGFR) inhibitors, gefitinib, erlotinib, cetuximab, and panitumumab, have been approved and have become standard-ofcare for use in patients with cancer. The activity reported in unselected patients has been quite limited. Those patients who achieve clinical benefit typically develop drug resistance [1,2,3]. The extent of intrinsic and acquired resistance to EGFR inhibitors leaves ample room for further anticancer drug development. Massachusetts; and 2Institut de Recherche en Cancerologie de Montpellier (IRCM), Institut National de la Sante et de la Recherche Medicale (INSERM), U896, Universite Montpellier I, Montpellier, France
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
