Targeting aurora kinases: a novel approach to curb the growth & chemoresistance of androgen refractory prostate cancer.
Aurora Kinase (AK) based therapy targeting AK-A & B is effective against some cancers. We have explored its potential against previously unreported incurable, metastatic androgen depletion independent Prostate Cancer (ADIPC). We used androgen sensitive (AS) and ADI lines derived from Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. The relevance of this model was unequivocally established through focussed array, quantitative PCR and western blotting studies; significantly greater alteration of genes (fold change and number) representing major cancer pathways was shown in ADI cells compared to AS lines. A marked enhancement of in vivo growth of the ADI subline showing the greatest degree of gene modulations [TRAMP C1 (TC1)-T5: TC1-T5] reflected this. In contrast to the parental AS TC1 line, TC1-T5 cells grew with 100% incidence in the prostate, as lung pseudometastases and migrated to the bone and other soft tissues. The potential involvement of AKs in this transition was indicated by the significant upregulation of AK-A/B and their downstream regulators, survivin and phosphorylated-histone H3 in TC1-T5 cells compared to TC1 cells. This led to enhanced sensitivity of TC1-T5 cells to the pan-AK inhibitor, VX680 and to significant reduction in in vivo tumour growth rates when AK-A and/or B were downregulated in TC1-T5 cells. This cell growth inhibition was markedly enhanced when both AKs were downregulated and also led to substantially greater sensitivity of these cells to docetaxel, the only chemotherapeutic with activity against ADI PC. Finally, use of VX680 with docetaxel led to impressive synergies suggesting promise for treating clinical ADI metastatic PC.
Oncology Research Centre, Prince of Wales Clinical School Research Laboratories, Clinical Science, Prince of Wales Hospital, Barker Street, Randwick, NSW#2031, Australia.
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V
Jeet
P J
PJ
Russell
N D
ND
Verma
A
A
Khatri
D000728:Androgens / Q000627:therapeutic use*; D000818:Animals; D064127:Aurora Kinases; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D010879:Piperazines / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000378:metabolism; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D043823:Taxoids / Q000494:pharmacology; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D000728:Androgens; D064127:Aurora Kinases; D000077143:Docetaxel; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D043823:Taxoids; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines