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Background Lung cancer is the leading cause of cancer death in the United States. Despite advances in cancer treatments, 85% of patients diagnosed with lung cancer will succumb to the disease. Bone morphogenetic proteins 2 and 4 (BMP2/4) are highly conserved embryonic proteins required for normal development and regulate the survival, migration, and cell fate decisions of stem cells [1, 2]. BMP signaling is not active in adult lung tissue but is reactivated in lung carcinoma and lung inflammation [2, 3]. The majority of non-small cell lung carcinomas (NSCLC) highly overexpress the BMP2 ligand [4]. BMP signaling in lung cancer regulates cell survival, migration, proliferation, stemness, angiogenesis, and ligand overexpression and is correlated with a worse prognosis [3, 5–8]. BMP signaling stimulates tumorigenesis in many carcinomas including prostate [9], breast [10, 11], pancreatic [12], melanoma, and sarcoma [13]. The BMP receptors are expressed in all NSCLC and inactivating mutations are infrequent [14]. There are over 20 BMP ligands that signal through serine/threonine kinases. The BMP ligands bind to the BMP type I receptors (ALK2, ALK3, or ALK6) [15], which are phosphorylated by the constitutively active BMP type 2 receptors (BMPR2, ActR-IIA, ActR-IIB) [15]. The BMP receptor complex then phosphorylates Smad 1/5 [16], which then translocates to the nucleus, transcriptionally regulating downstream targets including the inhibitor of differentiation proteins (ID1, ID2, and ID3) [17, 18]. The BMP signaling cascade also regulates Smad 1/5independent mechanisms. Smad 1/5-independent signaling occurs by the binding of proteins to the cytosolic tail of the BMP receptor. BMP regulation of cancer cell survival involves the regulation of X chromosome-linked inhibitor of apoptosis protein (XIAP) and transforming growth factor beta (TGFβ) activated kinase 1 (TAK1), an evolutionary conserved Smad 1/5-independent signaling pathway [19–21]. During embryonic development, BMPR2 regulates XIAP, which leads to the activation of TAK1 [22]. Both XIAP and TAK1 are potent inhibitors of cell death in cancer cells. XIAP inhibits apoptosis by binding to and inactivating effector caspases 3, 7, and 9 [23]. XIAP also functions as an E3 ligase inducing the degradation of caspases via the proteasome system [24]. TAK1 inhibits cell death by activating nuclear factorkappa beta (NF-κB) [25] and inhibits reactive oxygen species (ROS) production [26]. XIAP is being targeted as a cancer therapeutic because its inhibition of caspases promotes resistance to cancer therapeutics that induce apoptosis including tumour-necrosis factor (TNF)related apoptosis-inducing lingand (TRAIL) and various chemotherapeutics [23, 27, 28]. Several generations of small molecule inhibitors of BMP receptors have been derived from the same pyrazolo [1,5-a] pyrimidine core [29–31]. JL5 is an analog of DMH2, with improved pharmacokinetic properties compared to DMH2, that has been demonstrated to cause tumor regression of lung cancer xenografts [14, 20]. JL5 and DMH2 both cause a decrease in the expression of XIAP and a decrease in TAK1 activity [14, 20]. The mechanism by which the inhibition of BMP signaling decreases XIAP expression has not been fully elucidated.

cell communication and signaling

Targeting bone morphogenetic protein receptor 2 sensitizes lung cancer cells to TRAIL by increasing cytosolic Smac/DIABLO and the downregulation of X-linked inhibitor of apoptosis protein