Page 13 - H. Cell signaling

Development of a IGF-1R/Src/Axl inhibitor as a novel anticancer agent
with reduced toxicity

Ho Jin Lee, Honglan Pei, Seung Yeob Hyun,Hye-Young Min, Ho-Young Lee*
S eoul National University, Seoul 08826, Republic of Korea
abstract
The type I insulin-like growth factor receptor (IGF-1R) signaling pathway plays key roles in the development and progression of numerous
types of human cancers, and Src and AXL have been found to confer resistance to anti-IGF-1R therapies. Hence, co-targeting Src and AXL
may be an effective strategy to overcome resistance to anti-IGF-1R therapies. However, pharmacologic targeting of these three kinases may
result in enhanced toxicity. Therefore, the development of novel multitarget anticancer drugs that block IGF-1R, Src, and AXL is urgently
needed.

Method
To develop IGF-1R/Src/AXL-targeting small molecule kinase inhibitors, we selected compound6 as an active compound and evaluated its
antitumor and antimetastatic effects in vitro and in vivo using the MTT assay, colony formation assays, migration assay, flow cytometric
analysis, a tumor xenograft model, the KrasG12D/+-driven spontaneous lung tumorigenesis model. We also determined the toxicity of
compound6 in vitro and in vivo.

Results
1. Inhibitory effects of compound 6 on the viability, colony 2. Improved efficacy of conpound 6 compared with the
formation of several NSCLCs. concurrent blockade of IGF-1R and Src by treatment with a
A combination of linsitinib and dasatinib .
A
B
Com6(uM)
Com6(uM)

Com6(uM)
B
CT L/D com6 CT L/D com6 CT L/D com6
D

Com6(uM) C CT L/D com6
C
CT L/D com6 CT L/D com6

Com6(uM) Com6(uM) Com6(uM)

3. Minimal toxicity of compound 6 in vitro and in vivo. 4. Inhibitory effects on the growth of spontaneous lung
A tumorigenesis.

A

CT

D+L(uM) Com6(uM) D+L(uM) Com6(uM)
B C Com6

B

CT
Com6 20mg/kg
Com6 40mg/kg
Com6 80mg/kg
CT L/D com6 CT L/D com6
CT com6 CT com6 CT com6

Conclusion
Our results show the potential of LL6 as a novel IGF-1R/Src/AXL-targeting small molecule kinase inhibitor, providing a new avenue for
anticancer therapies.