Background
No targeted drugs are currently available against small cell lung cancer (SCLC). BCL-2
family members are involved in apoptosis regulation and represent therapeutic targets
in many malignancies.
Methods
Expression of BCL-2 family members in 27 SCLC cell lines representing all known four
SCLC molecular subtypes was assessed by qPCR, Western blot and mass spectrometry-based
proteomics. BCL-2 and MCL-1 inhibition (venetoclax and S63845, respectively) was assessed
by MTT assay and flow cytometry and in mice bearing human SCLC tumours. Drug interactions
were calculated using the Combenefit software. Ectopic BAX overexpression was achieved
by expression plasmids.
Results
The highest BCL-2 expression levels were detected in ASCL1- and POU2F3-driven SCLC
cells. Although sensitivity to venetoclax was reflected by BCL-2 levels, not all cell
lines responded consistently despite their high BCL-2 expression. MCL-1 overexpression
and low BAX levels were both characteristic for venetoclax resistance in SCLC, whereas
the expression of other BCL-2 family members did not affect therapeutic efficacy.
Combination of venetoclax and S63845 resulted in significant, synergistic in vitro
and in vivo anti-tumour activity and apoptosis induction in double-resistant cells;
however, this was seen only in a subset with detectable BAX. In non-responding cells,
ectopic BAX overexpression sensitised to venetoclax and S63845 and, furthermore, induced
synergistic drug interaction.
Conclusions
The current study reveals the subtype specificity of BCL-2 expression and sheds light
on the mechanism of venetoclax resistance in SCLC. Additionally, we provide preclinical
evidence that combined BCL-2 and MCL-1 targeting is an effective approach to overcome
venetoclax resistance in high BCL-2-expressing SCLCs with intact BAX.
