The present studies have examined approaches to suppress MCL-1 function in
breast cancer cells, as a means to promote
tumor cell death. Treatment of
breast cancer cells with CDK inhibitors (
flavopiridol;
roscovitine) enhanced the lethality of the ERBB1 inhibitor
lapatinib in a synergistic fashion. CDK inhibitors interacted with
lapatinib to reduce MCL-1 expression and over-expression of MCL-1 or knock down of BAX and BAK suppressed
drug combination lethality.
Lapatinib-mediated inhibition of ERK1/2 and to a lesser extent AKT facilitated CDK inhibitor -induced suppression of MCL-1 levels. Treatment of cells with the BH3 domain / MCL-1 inhibitor
obatoclax enhanced the lethality of
lapatinib in a synergistic fashion. Knock out of MCL-1 and BCL-XL enhanced
lapatinib toxicity to a similar extent as
obatoclax and suppressed the ability of
obatoclax to promote
lapatinib lethality. Pre-treatment of cells with
lapatinib or with
obatoclax enhanced basal levels of BAX and BAK activity and further enhanced
drug combination toxicity. In vivo
tumor growth data in xenograft and syngeneic model systems confirmed our in vitro findings. Treatment of cells with CDK inhibitors enhanced the lethality of
obatoclax in a synergistic fashion. Over-expression of MCL-1 or knock down of BAX and BAK suppressed the toxic interaction between CDK inhibitors and
obatoclax.
Obatoclax and
lapatinib treatment or
obatoclax and CDK inhibitor treatment or
lapatinib and CDK inhibitor treatment radiosensitized
breast cancer cells.
Lapatinib and
obatoclax interacted to suppress mammary
tumor growth in vivo. Collectively our data demonstrate that manipulation of MCL-1
protein expression by CDK inhibition or inhibition of sequestering function MCL-1 by
Obatoclax renders
breast cancer cells more susceptible to BAX/BAK-dependent
mitochondrial dysfunction and
tumor cell death.