Modelling Myc inhibition as a cancer therapy.
Myc is a pleiotropic basic helix-loop-helix leucine zipper transcription factor that coordinates expression of the diverse intracellular and extracellular programs that together are necessary for growth and expansion of somatic cells. In principle, this makes inhibition of Myc an attractive pharmacological approach for treating diverse types of cancer. However, enthusiasm has been muted by lack of direct evidence that Myc inhibition would be therapeutically efficacious, concerns that it would induce serious side effects by inhibiting proliferation of normal tissues, and practical difficulties in designing Myc inhibitory drugs. We have modelled genetically both the therapeutic impact and the side effects of systemic Myc inhibition in a preclinical mouse model of Ras-induced lung adenocarcinoma by reversible, systemic expression of a dominant-interfering Myc mutant. We show that Myc inhibition triggers rapid regression of incipient and established lung tumours, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumours in vivo. Systemic Myc inhibition also exerts profound effects on normal regenerating tissues. However, these effects are well tolerated over extended periods and rapidly and completely reversible. Our data demonstrate the feasibility of targeting Myc, a common downstream conduit for many oncogenic signals, as an effective, efficient and tumour-specific cancer therapy.
Soucek
Laura
L
Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143-0875, USA.
Whitfield
Jonathan
J
Martins
Carla P
CP
Finch
Andrew J
AJ
Murphy
Daniel J
DJ
Sodir
Nicole M
NM
Karnezis
Anthony N
AN
Swigart
Lamorna Brown
LB
Nasi
Sergio
S
Evan
Gerard I
GI
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000818:Animals; D041981:Gastrointestinal Tract / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D005799:Genes, Dominant / Q000235:genetics; D011905:Genes, ras; D015316:Genetic Therapy; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D013737:Testis / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D019076:Transgenes / Q000235:genetics
D016271:Proto-Oncogene Proteins c-myc; D015689:Oncogene Protein p21(ras)