Network rewiring, adaptive resistance and combating strategies in breast cancer

Abstract

Resistance to targeted anti-cancer drugs is a complex phenomenon and a major challenge in cancer treatment. It is becoming increasingly evident that a form of acquired drug resistance known as "adaptive resistance" is a common cause of treatment failure and patient relapse in many cancers. Unlike classical resistance mechanisms that are acquired via genomic alterations, adaptive resistance is instead driven by non-genomic changes involving rapid and dynamic rewiring of signalling and/or transcriptional networks following therapy, enabled by complex pathway crosstalk and feedback regulation. Such network rewiring allows tumour cells to adapt to the drug treatment, circumvent the initial drug challenge and continue to survive in the presence of the drug. Despite its great clinical importance, adaptive resistance remains largely under-studied and poorly defined. This review is focused on recent findings which provide new insights into the mechanisms underlying adaptive resistance in breast cancer, highlighting how breast tumour cells rewire intracellular signalling pathways to overcome the stress of initial targeted therapy. In particular, we investigate adaptive resistance to targeted inhibition of two major oncogenic signalling axes frequently dysregulated in breast cancer, the PI3K-AKT-mTOR and RAS-MAPK signalling pathways; and discuss potential combination treatment strategies that overcome such resistance. In addition, we highlight application of quantitative and computational modelling as a novel integrative and powerful approach to gain network-level understanding of network rewiring, and rationally identify and prioritise effective drug combinations.

Keywords: MAPK signalling; Network rewiring; PI3K signalling; adaptive resistance; breast cancer; mathematical modelling; systems analysis.

Figure 1

A: Frequency of alterations of PTEN and PIK3CA in breast cancer patients by subtype, analysed using the Pan-cancer Atlas dataset (n = 994) from The Cancer Genome Atlas Program (www.cbioportal.org); B: Signalling crosstalk between the PI3K and MAPK signalling pathways, with examples of targeted inhibitors directed at the network nodes

Figure 2

MEK inhibition dynamically reprograms the kinome and RTK signalling network. A: Inhibition of MEK disrupts a repressing transcriptional program exerted by the transcriptional factor c-Myc on the RTKs, which leads to induced expression and activation of an array of RTKs; B: MEK inhibition triggers a dynamic genome-wide enhancer formation with pronounced BRD4 density co-occupied with typical enhancer marks, causing increased expression and subsequent activation of RTKs, including PDGFRB, FGFR2, and DDR1

Figure 3

Adaptive upregulation of compensatory signalling limits the efficacy of EGFR-MAPK pathway inhibition. A: SHP2 is a convergent signalling node downstream of multiple RTKs. Inhibition of MEK induces SHP2 activation through increased RTK signalling and possibly other direct mechanisms, leading to ERK activity rebound. Inhibition of SHP2 prevents MEKi-induced ERK rebound through limiting the activity of RAS; B: upregulation of HER3 mediates adaptive resistance to EGFR in TNBC cells. PYK2 normally binds to the E3 ligase NEDD4 to inhibit it from degrading HER3. Inhibition of PYK2 destabilizes HER3 and resensitizes TBNC cells to EGFR inhibitors

Figure 4

Selective adaptive resistance mechanisms in response to PI3K pathway inhibition. A: A PTEN/Src/p130Cas signalling axis activates CRKL/p110β in PTEN-deficient tumour cells, providing a link between PTEN loss and activation of p110β in these cells (left). Specific PI3Kβ inhibition cause feedback upregulation of IRS1 and IGF1R which then activates the PI3Kα isoform and results in a rebound of PI3K signalling following transient suppression (right). The androgen receptor downstream of several RTKs also provides another escape mechanism for continued survival following PI3K inhibition; B: similar to MEK inhibition, PI3K inhibition also reprograms the transcriptional machinery controlled by BRD4, leading to induced upregulation of multiple RTKs and MYC; C: a ubiquitin-based mechanism of adaptive resistance to PI3K inhibition mediated by the E3 ubiquitin ligase Skp2. PI3K inhibition leads to increased Skp2 expression and activity, which ubiquitinates and enhances the activation of AKT