Abstract
Despite success of ERBB2-targeted therapies such as lapatinib, resistance remains a major clinical concern. Multiple compensatory receptor tyrosine kinase (RTK) pathways are known to contribute to lapatinib resistance. The heterogeneity of these adaptive responses is a significant hurdle for finding most effective combinatorial treatments. The goal of this study was to identify a unifying molecular mechanism whose targeting could help prevent and/or overcome lapatinib resistance. Using the MMTV-ERBB2;mutant p53 (R175H) in vivo mouse model of ERBB2-positive breast cancer, together with mouse and human cell lines, we compared lapatinib-resistant vs. lapatinib-sensitive tumor cells biochemically and by kinome arrays and evaluated their viability in response to a variety of compounds affecting heat shock response. We found that multiple adaptive RTKs are activated in lapatinib-resistant cells in vivo, some of which have been previously described (Axl, MET) and some were novel (PDGFRα, PDGFRβ, VEGFR1, MUSK, NFGR). Strikingly, all lapatinib-resistant cells show chronically activated HSF1 and its transcriptional targets, heat shock proteins (HSPs), and, as a result, superior tolerance to proteotoxic stress. Importantly, lapatinib-resistant tumors and cells retained sensitivity to Hsp90 and HSF1 inhibitors, both in vitro and in vivo, thus providing a unifying and actionable therapeutic node. Indeed, HSF1 inhibition simultaneously downregulated ERBB2, adaptive RTKs and mutant p53, and its combination with lapatinib prevented development of lapatinib resistance in vitro. Thus, the kinome adaptation in lapatinib-resistant ERBB2-positive breast cancer cells is governed, at least in part, by HSF1-mediated heat shock pathway, providing a novel potential intervention strategy to combat resistance.
Highlights
Human epidermal growth factor receptor 2 (Her[2], ERBB2) is overexpressed in about 25% of sporadic human breast cancer cases, which correlates with poor prognosis[1]
Generation and characterization of human and mouse lapatinib-resistant ERBB2-positive breast cancer cell lines To gain the mechanistic insight into lapatinib resistance we utilized two complementary approaches: in vitro and in vivo
Hsp[90] inhibition Since the majority of adaptive receptor tyrosine kinase (RTK) that we identified in vivo (Fig. 1f) are known Hsp[90] clients, we hypothesized that lapatinib-resistant cells retain their sensitivity to Hsp[90] inhibitors
Summary
Human epidermal growth factor receptor 2 (Her[2], ERBB2) is overexpressed in about 25% of sporadic human breast cancer cases, which correlates with poor prognosis[1]. Multiple mechanisms of lapatinib resistance are described in the literature. They primarily involve compensatory activation of receptor tyrosine kinases (RTKs), such as ERBB3, IGF1R, MET, FGFR2, FAK, Axl, as well as other mechanisms[2]. Not a single, but multiple RTKs have been shown to be activated in response to lapatinib[3]. The substantial heterogeneity among adaptive RTKs exists in different cell lines in response to lapatinib[3]. This represents a major hurdle for the development of successful combinatorial strategies to reverse and/or prevent lapatinib resistance. Identification and targeting of an upstream effector governing the kinome adaption in response to ERBB2 inhibition would help to overcome this clinical dilemma
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