# BMP receptor 2 inhibition regulates mitochondrial bioenergetics to induce synergistic cell death with BCL-2 inhibitors in leukemia and NSLC cells

## TL;DR

Blocking BMP receptor 2 boosts mitochondrial activity and enhances cancer drug effects in lung cancer and leukemia cells.

## Contribution

BMPR2 inhibition synergizes with BCL-2 inhibitors to induce cell death via mitochondrial Ca++ and ROS in leukemia and NSLC.

## Key findings

- BMPR2 inhibition increases mitochondrial Ca++ and bioenergetics in NSLC and leukemia cells.
- BMPR2i synergizes with BCL-2 inhibitors to cause cell death via increased ROS and Ca++.
- AML and T-cell leukemia cells are more responsive to BMPR2i and BCL-2 inhibitor combinations.

## Abstract

Bone morphogenetic protein (BMP) signaling cascade is a phylogenetically conserved stem cell regulator that is aberrantly expressed in non-small cell lung cancer (NSLC) and leukemias. BMP signaling negatively regulates mitochondrial bioenergetics in lung cancer cells. The impact of inhibiting BMP signaling on mitochondrial bioenergetics and the effect this has on the survival of NSLC and leukemia cells are not known.

Utilizing the BMP type 2 receptor (BMPR2) JL189, BMPR2 knockout (KO) in cancer cells, and BMP loss of function mutants in C elegans, we determined the effects of BMPR2 inhibition (BMPR2i) on TCA cycle metabolic intermediates, mitochondrial respiration, and the regulation of mitochondrial superoxide anion (SOA) and Ca++ levels. We also examined whether BMPR2i altered the threshold cancer therapeutics induce cell death in NSLC and leukemia cell lines. KO of the mitochondria uniporter (MCU) was used to determine the mechanism BMPR2i regulates the uptake of Ca++ into the mitochondria, mitochondrial bioenergetics, and cell death.

BMPR2i increases mtCa++ levels and enhances mitochondrial bioenergetics in both NSLC and leukemia cell lines that is conserved in C elegans. BMPR2i induced increase in mtCa++ levels is regulated through the MCU, effecting mitochondria mass and cell survival. BMPR2i synergistically induced cell death when combined with BCL-2 inhibitors or microtubule targeting agents in both NSLC and leukemia cells. Cell death is caused by synergistic increase in mitochondrial ROS and Ca++ levels. BMPR2i enhances Ca++ uptake into the mitochondria induced by reactive oxygen species (ROS) produced by cancer therapeutics. Both acute myeloid leukemia (AML) and T-cell lymphoblastic leukemia cells lines were more responsive to the JL189 alone and when combined with venetoclax or navitoclax compared to NSLC.