Is there potential to target FOXM1 for 'undruggable' lung cancers?
Published studies with transgenic mice convincingly showed that Forkhead Box transcription factor M1 (FOXM1) transcription factor is an important component of the KRAS/ERK signaling pathway in respiratory epithelial cells. FOXM1 is required for oncogenic KRAS signaling in mouse lung cancer models and therefore, clear potential exists to target FOXM1 in human NSCLC driven by activated KRAS mutations. To date, several approaches to inhibit FOXM1 in cancer cells have been explored. These include siRNA/shRNA-mediated inhibition of Foxm1 mRNA, sequestration of FOXM1 protein in nucleoli using ARF peptide, inhibition of FOXM1 binding to its target promoter DNAs by the FDI-6 small-molecule compound and inhibition of proteasomes by thiazole antibiotics. Additional studies are needed to determine if inhibition of FOXM1 is beneficial for treatment of KRAS mutant NSCLCs in human patients and to develop effective delivery systems for FOXM1 inhibitors. If successful, additional strategies can be explored to screen for novel FOXM1 inhibitors, such as targeting FOXM1 nuclear localization, nuclear export or protein-protein interactions with activating kinases and co-activator proteins. Altogether, inhibition of FOXM1, either alone or in combination with other anticancer drugs, could be beneficial for treatment of KRAS mutant NSCLCs that are resistant to conventional chemotherapy.
Cincinnati Children's Hospital Medical Center, Division of Pulmonary Biology , 3333 Burnet Ave, MLC 7009, Cincinnati, OH 45229 , USA +1 513 636 4822 ; +1 513 636 2423 ; Vladimir.Kalinichenko@cchmc.org.
Vladimir V
VV
Kalinichenko
Tanya V
TV
Kalin
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology
D000970:Antineoplastic Agents; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
FOXM1; KRAS; NSCLC; transgenic mice