Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cellsin vitroandin vivo

// Laurence Booth 1 , Thomas Albers 3 , Jane L. Roberts 1 , Mehrad Tavallai 1 , Andrew Poklepovic 2 , Iryna O. Lebedyeva 3 , Paul Dent 1 1 Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA 2 Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA 3 Department of Chemistry and Physics, Augusta University, Summerville Campus, Augusta GA 30912, USA Correspondence to: Paul Dent, email: pdent@vcu.edu Keywords: sorafenib, pazopanib, chaperones, ERBB, PI3K Received: April 25, 2016      Accepted: May 20, 2016      Published: May 31, 2016 ABSTRACT We have recently demonstrated that multi-kinase inhibitors such as sorafenib and pazopanib can suppress the detection of chaperones by in situ immuno-fluorescence, which is further enhanced by phosphodiesterase 5 inhibitors. Sorafenib and pazopanib inhibited the HSP90 ATPase activity with IC50 values of ~1.0 μM and ~75 nM, respectively. Pazopanib docked in silico with two possible poses into the HSP90 ATP binding pocket. Pazopanib and sildenafil combined to reduce the total protein levels of HSP1H/p105 and c-MYC and to reduce their co-localization. Sorafenib/pazopanib combined with sildenafil in a [GRP78+HSP27] –dependent fashion to: (i) profoundly activate an eIF2α/Beclin1 pathway; (ii) profoundly inactivate mTOR and increase ATG13 phosphorylation, collectively resulting in the formation of toxic autophagosomes. In a fresh PDX isolate of NSCLC combined knock down of [ERBB1+ERBB3] or use of the ERBB1/2/4 inhibitor afatinib altered cell morphology, enhanced ATG13 phosphorylation, inactivated NFκB, and further enhanced [sorafenib/pazopanib + sildenafil] lethality. Identical data to that with afatinib were obtained knocking down PI3K p110α/β or using buparlisib, copanlisib or the specific p110α inhibitor BYL719. Afatinib adapted NSCLC clones were resistant to buparlisib or copanlisib but were more sensitive than control clones to [sorafenib + sildenafil] or [pazopanib + sildenafil]. Lapatinib significantly enhanced the anti-tumor effect of [regorafenib + sildenafil] in vivo ; afatinib and BYL719 enhanced the anti-tumor effects of [sorafenib + sildenafil] and [pazopanib] in vivo , respectively.