Download Tumor Microenvironment: A New Treatment Target to overcome

Tumor Microenvironment: A New Treatment Target to overcome Resistance to
Anticancer Therapy
Ho-Young Lee
College of Pharmacy, Seoul National University, Seoul, Republic of Korea
Drug resistance is a major impediment in medical oncology. Recent studies have emphasized
the importance of the tumor microenvironment (TME) to innate resistance to molecular
targeted therapies. The type 1 insulin-like growth factor receptor (IGF-1R)-mediated signaling
is known to be crucial for cell growth, survival and has been considered as an attractive target
for developing molecularly targeted anticancer therapy. Several clinical trials have been
conducted to evaluate the efficacy of IGF-1R-targeted anticancer agents such as monoclonal
antibodies (mAbs) and small molecule tyrosine kinase inhibitors (TKIs); however, most of these
trials did not show clinical benefits and the further clinical development of many IGF-1R
targeted drugs has halted. Recently, we discovered a novel molecular mechanisms underlying
resistance to cixutumumab, a fully humanized mAb against IGF-1R, in relation to modulation
of TME. In orthotopic and subcutaneous tumor xenograft models using human non-small cell
lung cancer (NSCLC) and breast cancer cells, we observed that cixutumumab treatment
displayed either no change or increased tumor growth with recruitment of surrounding stromal
cells, eventually leading to decreased survival of mice. The metastatic tumor formation was
confirmed in the orthotopic xenograft model using humanized mice. Further studies
demonstrated that cixutumumab treatment activated STAT3 and transcriptionally up-regulated
IGF2 in cancer cells. IGF2 further mediated interaction with fibroblasts and monocytes via IGF2R, thereby inducing CXCL8 production in these cells and eventually leading to recruitment of
vascular endothelial cells, angiogenesis, and metastasis. Silencing IGF2 or STAT3 expression
in cancer cells or IGF-2R or CXCL8 expression in stromal cells significantly inhibited the
cancer-stroma communication and angiogenesis. These results suggest that blocking the
STAT3/IGF-2/IGF-2R intercellular signaling loop may overcome the adverse consequences of
anti-IGF-1R mAb-based therapies.