ERK Phosphorylation Is Predictive of Resistance to IGF-1R Inhibition in Small Cell Lung Cancer

Abstract

New therapies are critically needed to improve the outcome for patients with small cell lung cancer (SCLC). IGF-1R inhibition is a potential treatment strategy for SCLC: the IGF-1R pathway is commonly upregulated in SCLC, and has been associated with inhibition of apoptosis and stimulation of proliferation through downstream signaling pathways including PI3K-Akt and MAPK. To evaluate potential determinants of response to IGF-1R inhibition, we assessed the relative sensitivity of 19 SCLC cell lines to OSI-906, a small molecule inhibitor of IGF-1R and the closely related insulin receptor (IR). Approximately one third of these cell lines were sensitive to OSI-906, with an IC50 < 1 μM. Cell line expression of IGF-1R, IR, IGF-1, IGF-2, IGFBP3, and IGFBP6 did not correlate with sensitivity to OSI-906. Interestingly, OSI-906 sensitive lines expressed significantly lower levels of baseline phospho-ERK relative to resistant lines (p=0.006). OSI-906 treatment resulted in dose-dependent inhibition of phospho-IGF-1R and phospho-Akt in both sensitive and resistant cell lines, but induced apoptosis and cell cycle arrest only in sensitive lines. We tested the in vivo efficacy of OSI-906 using an NCI-H187 xenograft model and two SCLC patient xenografts in mice. OSI-906 treatment resulted in 50% tumor growth inhibition in NCI-H187 and 30% inhibition in the primary patient xenograft models compared to mock treated animals. Taken together our data support IGF-1R inhibition as a viable treatment strategy for a defined subset of SCLC and suggest that low pretreatment levels of phospho-ERK may be indicative of sensitivity to this therapeutic approach.

Trabectedin Efficacy in Ewing Sarcoma Is Greatly Increased by Combination with Anti-IGF Signaling Agents

“…From a clinical point of view, increased expression of IGF1R in response to in vitro and in vivo exposure to trabectedin, provides the rationale for a combined use of trabectedin with anti-IGF1R agents. Here, we demonstrate the advantages of this combination either using HAb AVE1642, a well-tolerated agent that binds human IGF1R specifically and with high affinity (45,46), or the dual inhibitor IGF1R/IR, OSI-906, a small molecule shown to have antitumoral activity against several tumors (47,48), including osteosarcoma (49). The association of OSI-906 with trabectedin gave synergistic effects in all of the 13 EWS cell lines here considered, including cells resistant to trabectedin (18) or to anti-IGF1R agents (29).…”

Is the Canonical RAF/MEK/ERK Signaling Pathway a Therapeutic Target in SCLC?

“…As a single agent, IGF-1R inhibitors may have some activity in a subset of SCLC tumors. Interestingly, resistance to these inhibitors correlates with increased phospho-ERK1/2 levels, suggesting that the RAF-MEK-ERK pathway is a key mediator of IGF-1/IGF-1R signaling in SCLC cells 39 , and raising the possibility that a combination therapy inhibiting MEK activity could enhance the anti-tumor effects of an anti-IGF-1R monoclonal antibody 40 . This combination therapy may be especially valid given data in lung adenocarcinoma cells that IGF-1 and IGF-1R are important for the emergence of drug tolerance following inhibition of the upstream MAPK signaling pathway by an EGFR inhibitor 41 .…”

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

“…While PTEN loss amplifies signalling to AKT, it does not induce constitutive pathway activation; logic dictates that constitutively activating mutations in the PI3K-AKT or RAS-RAF-ERK pathways should render cells refractory to IGF axis blockade. Indeed, preclinical data suggest that resistance to IGF-1R inhibition is observed in the context of constitutive AKT activation and high levels of activated ERKs [108–111], and sensitivity of KRAS mutant NSCLC was restored by MEK inhibition [112,113]. Consistent with this, IGF-1R antibody ganitumab was ineffective at sensitizing to FOLFIRI chemotherapy in patients with KRAS mutant colorectal cancer [114], although issues of chemotherapy scheduling may be a contributing factor (see below).…”