TMEM16A/ANO1 suppression improves response to antibody-mediated targeted therapy of EGFR and HER2/ERBB2.
TMEM16A, a Ca2+-activated Cl-channel, contributes to tumor growth in breast cancer and head and neck squamous cell carcinoma (HNSCC). Here, we investigated whether TMEM16A influences the response to EGFR/HER family-targeting biological therapies. Inhibition of TMEM16A Cl-channel activity in breast cancer cells with HER2 amplification induced a loss of viability. Cells resistant to trastuzumab, a monoclonal antibody targeting HER2, showed an increase in TMEM16A expression and heightened sensitivity to Cl-channel inhibition. Treatment of HNSCC cells with cetuximab, a monoclonal antibody targeting EGFR, and simultaneous TMEM16A suppression led to a pronounced loss of viability. Biochemical analyses of cells subjected to TMEM16A inhibitors or expressing chloride-deficient forms of TMEM16A provide further evidence that TMEM16A channel function may play a role in regulating EGFR/HER2 signaling. These data demonstrate that TMEM16A regulates EGFR and HER2 in growth and survival pathways. Furthermore, in the absence of TMEM16A cotargeting, tumor cells may acquire resistance to EGFR/HER inhibitors. Finally, targeting TMEM16A improves response to biological therapies targeting EGFR/HER family members.
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.|Veterans Affairs Pittsburgh Health System, Pittsburgh, Pennsylvania.
Sucheta
S
Kulkarni
Novartis Institute for Biomedical Research, Cambridge, MA, 02139.
Anke
A
Bill
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Neal R
NR
Godse
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Nayel I
NI
Khan
Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Jason I
JI
Kass
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Kevin
K
Steehler
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.|Veterans Affairs Pittsburgh Health System, Pittsburgh, Pennsylvania.
Carolyn
C
Kemp
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Kara
K
Davis
Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Carol A
CA
Bertrand
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Avani R
AR
Vyas
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Douglas E
DE
Holt
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Jennifer R
JR
Grandis
Novartis Institute for Biomedical Research, Cambridge, MA, 02139.
L Alex
LA
Gaither
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.|Veterans Affairs Pittsburgh Health System, Pittsburgh, Pennsylvania.
Umamaheswar
0000-0003-1968-3756
U
Duvvuri
D000818:Animals; D000075369:Anoctamin-1; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000627:therapeutic use*; D018118:Chloride Channels / Q000235:genetics* / Q000276:immunology; D002880:Chromosomes, Human, Pair 11; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics* / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D000077195:Squamous Cell Carcinoma of Head and Neck; D000068878:Trastuzumab / Q000627:therapeutic use*
D000075369:Anoctamin-1; D000068818:Cetuximab; D018118:Chloride Channels; D066246:ErbB Receptors; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C476213:ANO1 protein, human