The Janus Kinases Inhibitor AZD1480 Attenuates Growth of Small Cell Lung Cancers In Vitro and In Vivo

Abstract

Purpose The prognosis of small cell lung cancer (SCLC) is poor, and there has been very little progress in the medical treatment of SCLC in the past two decades. We investigated the potential of janus kinases (JAKs) inhibitor AZD1480 for treatment of SCLC in vitro and in vivo. Experimental Design JAK1 or JAK2 were inhibited by AZD1480 or siRNAs, and the effect of inhibition of JAK gene family on SCLC cell viability was evaluated. The effect of AZD1480 on cell cycle distribution and apoptosis induction were studied. Antitumor effects of AZD1480 in tumor xenografts were assessed. Results AZD1480 significantly inhibited growth of 6 out of 13 SCLC cells with IC50s ranging from 0.73 to 3.08 μM. Knocking-down of JAK2 and JAK1 inhibited proliferation of Jak2-positive/Jak1-negative H82 cells and Jak1-positive/Jak2-negative GLC4 cells, respectively. Treatment of SCLC cells with AZD1480 for 24 hours resulted in increase of 4N DNA content and Histone 3 serine 10 phosphorylation, indicative of G2/M phase arrest. Moreover, SCLCs underwent apoptosis after AZD1480 treatment as exemplified by the downregulation of MCL1, the accumulation of cleaved-Caspase 3, cleaved PARP and increase of annexin-V positive cells. Finally, xenograft experiments showed that AZD1480 attenuated the growth of H82 and GLC4 tumors in mice, and we observed stronger apoptosis as well as decreased CD31 positive endothelial cells in H82 and GLC4 xenografts upon AZD1480 treatment. Conclusions Janus kinases inhibitor AZD1480 attenuated growth of SCLC cells in vitro and in vivo. Clinical development of anti-JAKs therapies in SCLC warrants further investigation.

Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?

“…In vitro and animal data indicates that targeting JAK2 with siRNA will inhibit the growth of SCLC. AZD1480 (which targets JAK1/2/3, FLT3 and Aurora kinase) has single agent activity as well as synergy with existing chemotherapy 91 .…”

Role of STAT3 in lung cancer

“…For example, the JAK2 inhibitor AZD1480 blocks STAT3 activation in several solid tumor cell lines, including several small and nonsmall cell lung cancer cell lines, and suppresses the growth cancer xenografts harboring persistent STAT3 activation. [115][116][117] In NSCLC cells, IL-6 neutralizing antibody has been shown to inhibit tumor growth in a mouse xenograft model by suppressing JAK1/STAT3 signaling. 50 Moreover, the JAK1/2 inhibitor ruxolitinib significantly slowed down the growth of xenografted NSCLC cells in nude mice.…”

MEDICI: Mining Essentiality Data to Identify Critical Interactions for Cancer Drug Target Discovery and Development

“…Of those 15 PPIs, six included JAK1 as a binding partner, two included JAK2, and one was the JAK1-JAK2 interaction. It has recently been shown that inhibition of JAKs attenuates growth of small cell lung cancers in vitro and in vivo [58], and that activation of JAK signaling induces resistance to EGFR mutations in non-small cell lung cancers [59]. Also of potential interest is an ATM-NBN interaction that is involved in double-strand DNA break repair and PI3KR1 interactions involved in activation of the PI3K pathway.…”