Mutant p53 Modulates the Signal of Stromal-Secreted Hepatocyte Growth Factor (HGF) to Endow Cancer Cells with Drug Resistance

Drug resistance is a major obstacle in cancer therapy. Recently, a co-cultivation screen identified a major role of the microenvironment in promoting drug resistance in various solid tumors¹. Mutations in the p53 tumor suppressor protein are highly frequent in tumors and often endow cells with tumorigenic capacities. However, the role of mutant p53 in the context of tumor-stroma interaction has not been thoroughly studied yet. In this study, we performed a cytokine screen, to identify potential secreted molecules which endow the cancer cells with drug resistance, in a mutant p53 dependent manner. We established isogenic lung cancer sub-lines, harboring different p53 statuses and labeled with tRFP. After treating these sub-lines with EGFR inhibitor and a cytokine library, we identified several potential cytokines which endow the mutant p53 expressing sub-line with enhanced resistance compared to mutant p53-knocked down sub-line. Remarkably, the most significant factor endowing drug resistance in a mutant p53 dependent manner was hepatocyte growth factor (HGF, see attached figure) , which was previously shown to be a major contributor to innate resistance to RAF inhibitors¹. We therefore demonstrate a potential role for mutant p53 in modulating stromal-derived signals to promote drug resistance in the tumor cells. In a broad sense, we demonstrate how a cancer cell determinant can manipulate a stromal signal for the tumor’s benefit.

Reference

1. Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–4 (2012).