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Neratinib augments the lethality of [regorafenib + sildenafil]
Author(s) -
Booth Laurence,
Roberts Jane L.,
Rais Rumeesa,
Cutler Richard E.,
Diala Irmina,
Lalani Alshad S.,
Hancock John F.,
Poklepovic Andrew,
Dent Paul
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.27276
Subject(s) - regorafenib , cancer research , neratinib , pharmacology , protein kinase b , pi3k/akt/mtor pathway , chemistry , medicine , biology , microbiology and biotechnology , colorectal cancer , signal transduction , cancer , trastuzumab , breast cancer
Regorafenib is approved for the treatment of colorectal cancer and hepatocellular carcinoma. In the trial NCT02466802, we have discovered that regorafenib can be safely combined with the phosphodiesterase 5 inhibitor sildenafil in advanced solid tumor patients. The present studies determined whether the approved ERBB1/2/4 and RAS downregulating drug neratinib, could enhance the lethality of [regorafenib + sildenafil]. Neratinib enhanced [regorafenib + sildenafil] lethality in a greater than additive fashion in colon cancer cells. The drug combination reduced the expression of mutant K‐RAS and of multiple histone deacetylase (HDAC) proteins that required autophagosome formation. It caused green fluorescent protein or red fluorescent protein–tagged forms of K‐RAS V12 to localize into large intracellular vesicles. Compared with [regorafenib + sildenafil], the three‐drug combination caused greater and more prolonged activation of the ATM‐AMPK‐ULK‐1 pathway and caused a greater suppression and prolonged inactivation of mammalian target of rapamycin, AKT, and p70 S6K. Approximately 70% of enhanced lethality caused by neratinib required ataxia‐telangiectasia‐mutated (ATM)–AMP‐dependent protein kinase (AMPK) signaling whereas knockdown of Beclin1, ATG5, FADD, and CD95 completely prevented the elevated killing effect. Exposure of cells to [regorafenib + sildenafil] reduced the expression of the checkpoint immunotherapy biomarkers programmed death‐ligand 1, ornithine decarboxylase, and indoleamine 2,3‐dioxygenase‐1 and increased the expression of major histocompatibility complex A (MHCA), which also required autophagosome formation. Knockdown of specific HDAC proteins recapitulated the effects observed using chemical agents. In vivo, using mouse cancer models, neratinib significantly enhanced the antitumor efficacy of [regorafenib + sildenafil]. Our data support performing a new three drug Phase I trial combining regorafenib, sildenafil, and neratinib.