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2016 ; 7
(34
): 54897-54912
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PIM kinases as therapeutic targets against advanced melanoma
#MMPMID27448973
Shannan B
; Watters A
; Chen Q
; Mollin S
; Dörr M
; Meggers E
; Xu X
; Gimotty PA
; Perego M
; Li L
; Benci J
; Krepler C
; Brafford P
; Zhang J
; Wei Z
; Zhang G
; Liu Q
; Yin X
; Nathanson KL
; Herlyn M
; Vultur A
Oncotarget
2016[Aug]; 7
(34
): 54897-54912
PMID27448973
show ga
Therapeutic strategies for the treatment of metastatic melanoma show encouraging
results in the clinic; however, not all patients respond equally and tumor
resistance still poses a challenge. To identify novel therapeutic targets for
melanoma, we screened a panel of structurally diverse organometallic inhibitors
against human-derived normal and melanoma cells. We observed that a compound that
targets PIM kinases (a family of Ser/Thr kinases) preferentially inhibited
melanoma cell proliferation, invasion, and viability in adherent and
three-dimensional (3D) melanoma models. Assessment of tumor tissue from melanoma
patients showed that PIM kinases are expressed in pre- and post-treatment tumors,
suggesting PIM kinases as promising targets in the clinic. Using knockdown
studies, we showed that PIM1 contributes to melanoma cell proliferation and tumor
growth in vivo; however, the presence of PIM2 and PIM3 could also influence the
outcome. The inhibition of all PIM isoforms using SGI-1776 (a
clinically-available PIM inhibitor) reduced melanoma proliferation and survival
in preclinical models of melanoma. This was potentiated in the presence of the
BRAF inhibitor PLX4720 and in the presence of PI3K inhibitors. Our findings
suggest that PIM inhibitors provide promising additions to the targeted therapies
available to melanoma patients.
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