Targeting anti-apoptosis as a therapeutic strategy in neuroendocrine neoplasms

BCL-2 is an anti-apoptotic protein expressed by aggressive neuroendocrine neoplasms (NENs). We report a case of a patient with a pancreatic neuroendocrine tumor (pNET) who received venetoclax, a BCL-2 targeting drug for the treatment of chronic lymphocytic leukemia. We further characterized BCL2 expression in NENs from a large multi-institutional patient cohort. Clinical data was abstracted from the records of a patient with a pNET. Next-generation sequencing of DNA (592-gene panel or whole exome) and RNA (whole transcriptome) was performed on 636 NENs of pancreatic (P-NENs), small bowel (SB-NENs), colorectal (CR-NENs), and lung (L-NENs) origin by Caris Life Sciences. Comparisons were performed against site-matched non-NEN cancers. BCL2- or MKI67- high and low cohorts were defined based on the top and bottom quartiles of gene expression. We found that the patient with a pNET who received venetoclax had a partial response in the primary tumor that lasted 30 months. CR-, L- and P-NENs had significantly higher expression of BCL2 compared to non-NEN counterparts. BCL2 expression was significantly higher in MKI67-high tumors among all NEN subtypes. In P-NENs, there was a higher prevalence of RB1 mutations in BCL2-high vs. BCL2-low (40 vs. 4.9%, P < 0.005). Patients with BCL2-high P-NENs had significantly decreased overall survival (HR 1.94, 95% CI 1.0 -3.76, P = 0.047). Immune checkpoint gene expression and T cells were enriched in BCL2-high tumors across all subtypes. We report the first known case of a pancreatic NET with response to venetoclax. BCL2 expression correlated with high MKI67 expression, worse survival, and a highly immune-enriched microenvironment.