IGF1R upregulation confers resistance to isoform-specific inhibitors of PI3K in PIK3CA-driven ovarian cancer

Jonatan Zorea,Moshe Elkabets,Nan Li,Limor Cohen,Roman Schefzik,Susmita Ghosh,Benedikt Brors,Barak Rotblat,Manu Prasad

doi:10.1038/s41419-018-1025-8

Abstract

Genomic alterations (GA) in PIK3CA leads to the hyper-activation of the phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) pathway in more than 20% of ovarian cancer (OC) patients. Therefore, PI3K therapies are under clinical evaluation for this subset of patients. Evidently, in clinical trials testing the efficacy of isoform-specific inhibitors of PI3K (PI3Ki), patients having a stable disease eventually relapse, as tumors become resistant to treatment. Hence, there is an urgent clinical need to develop new therapeutic combinations to improve the efficacy of PI3Ki in PIK3CA-driven OC patients. Here we identified the molecular mechanism that limits the efficacy of the beta-sparing PI3Ki, Taselisib (GDC0032), in PIK3CA-mutated OC cell lines (IGROV1 and OAW42) that acquired resistance to GDC0032. By comparing the molecular profile of GDC0032-sensitve and -resistant OC cell lines, we found that AKT/mTOR inhibition is required for GDC0032 efficacy. In resistant cells, the sustained activation of AKT/mTOR was regulated by the upregulation of the insulin growth factor 1 receptor (IGF1R). Knockdown of IGF1R re-sensitized cells to GDC0032 in vitro, and the combination of AEW541, an IGF1R inhibitor, with GDC0032 exhibited potent anti-tumor activity in vitro and in vivo. We further demonstrated that IGF1R regulates tumor cell proliferation in IGROV1 cells, whereas in OAW42, it determines autophagy as well. Overall, our findings suggest that the dual inhibition of PI3K and IGF1R may be considered as a new therapeutic strategy in PIK3CA-driven OC.

Highlights

The phosphatidylinositol 3-kinase (PI3K) pathway is a key regulator of the survival, growth, and metabolism of normal and malignant cells[1,2]
Since PIK3CA-mutated cancer cells were found to be more sensitive to PI3Ki than were PIK3CA-wild-type cells[9,10,11,12,13,14,15,16,17,18], we explored the Cancer Cell Line Encyclopedia (CCLE) databases[21], searching for PI3Ki-sensitive ovarian cancer (OC) cell lines with genomic alterations (GA) in PIK3CA (Supplementary Fig. 1A)
In our acquired-resistant model, we found that overexpression of insulin growth factor 1 receptor (IGF1R) plays a major role in maintaining AKT/mTOR pathway activation

Summary

Introduction

The phosphatidylinositol 3-kinase (PI3K) pathway is a key regulator of the survival, growth, and metabolism of normal and malignant cells[1,2]. This pathway is often hyperactivated due to genomic alterations (GA) in PI3K pathway-related genes such as deletions in PTEN, and mutations or amplifications in PIK3CA, AKT3, AKT2, and AKT13–7. Cancer cells with GA in PIK3CA have been shown to be more susceptible to isoform-specific inhibitors of the PI3K pathway (PI3Ki) in vitro, in vivo, and in patients than tumor cells with wild-type PIK3CA9–19. GDC0032 has exhibited clinical activity in tumors harboring PIK3CA alterations in early clinical trials[14,15], but eventually all patients relapsed and developed resistance

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Results

Conclusion