Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship.
The goal of targeted therapy is to match a selective drug with a genetic lesion that predicts for drug sensitivity. In a diverse panel of cancer cell lines, we found that the cells most sensitive to focal adhesion kinase (FAK) inhibition lack expression of the neurofibromatosis type 2 (NF2) tumor suppressor gene product, Merlin. Merlin expression is often lost in malignant pleural mesothelioma (MPM), an asbestos-induced aggressive cancer with limited treatment options. Our data demonstrate that low Merlin expression predicts for increased sensitivity of MPM cells to a FAK inhibitor, VS-4718, in vitro and in tumor xenograft models. Disruption of MPM cell-cell or cell-extracellular matrix (ECM) contacts with blocking antibodies suggests that weak cell-cell adhesions in Merlin-negative MPM cells underlie their greater dependence on cell-ECM-induced FAK signaling. This provides one explanation of why Merlin-negative cells are vulnerable to FAK inhibitor treatment. Furthermore, we validated aldehyde dehydrogenase as a marker of cancer stem cells (CSCs) in MPM, a cell population thought to mediate tumor relapse after chemotherapy. Whereas pemetrexed and cisplatin, standard-of-care agents for MPM, enrich for CSCs, FAK inhibitor treatment preferentially eliminates these cells. These preclinical results provide the rationale for a clinical trial in MPM patients using a FAK inhibitor as a single agent after first-line chemotherapy. With this design, the FAK inhibitor could potentially induce a more durable clinical response through reduction of CSCs along with a strong antitumor effect. Furthermore, our data suggest that patients with Merlin-negative tumors may especially benefit from FAK inhibitor treatment.
Verastem Inc., Cambridge, MA 02142, USA.
Irina M
IM
Shapiro
Verastem Inc., Cambridge, MA 02142, USA.
Vihren N
VN
Kolev
Verastem Inc., Cambridge, MA 02142, USA.
Christian M
CM
Vidal
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Yuwaraj
Y
Kadariya
Verastem Inc., Cambridge, MA 02142, USA.
Jennifer E
JE
Ring
Verastem Inc., Cambridge, MA 02142, USA.
Quentin
Q
Wright
Verastem Inc., Cambridge, MA 02142, USA.
David T
DT
Weaver
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Craig
C
Menges
Verastem Inc., Cambridge, MA 02142, USA.
Mahesh
M
Padval
Massachusetts General Hospital Center for Cancer Research and Department of Pathology, Harvard Medical School, Charlestown, MA 02129, USA.
Andrea I
AI
McClatchey
Verastem Inc., Cambridge, MA 02142, USA.
Qunli
Q
Xu
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Joseph R
JR
Testa
Verastem Inc., Cambridge, MA 02142, USA. jpachter@verastem.com.
Jonathan A
JA
Pachter
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology; D025581:Neurofibromin 2 / Q000172:deficiency* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D025581:Neurofibromin 2; D047428:Protein Kinase Inhibitors; D000444:Aldehyde Dehydrogenase; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human