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Coupling an EML4-ALK–centric interactome with RNA interference identifies sensitizers to ALK inhibitors

Sci. Signal.  18 Oct 2016:
Vol. 9, Issue 450, pp. rs12
DOI: 10.1126/scisignal.aaf5011

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Networking ALK for combination therapies

Some lung cancers have high activity of the kinase ALK as the result of rearrangements between the genes EML4 and ALK. ALK inhibitors are effective in some patients, but resistance to single-agent therapy is common. Using phosphoproteomics and an RNA interference screen, Zhang et al. derived a signaling network mediated by ALK in EML4-ALK–rearranged lung cancer cell lines. From this network, they identified many candidates that could sensitize cells to ALK inhibition. Indeed, knocking down either of two of these two proteins, the scaffolding proteins FRS2 and CC2D1A, sensitized cell lines to the ALK inhibitors crizotinib and alectinib. Thus, a clinical strategy that inhibits FRS2 or CC2D1A might enhance the efficacy of ALK inhibitors in some patients.

Abstract

Patients with lung cancers harboring anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK inhibitors, but acquired resistance inevitably arises. A better understanding of proximal ALK signaling mechanisms may identify sensitizers to ALK inhibitors that disrupt the balance between prosurvival and proapoptotic effector signals. Using affinity purification coupled with mass spectrometry in an ALK fusion lung cancer cell line (H3122), we generated an ALK signaling network and investigated signaling activity using tyrosine phosphoproteomics. We identified a network of 464 proteins composed of subnetworks with differential response to ALK inhibitors. A small hairpin RNA screen targeting 407 proteins in this network revealed 64 and 9 proteins that when knocked down sensitized cells to crizotinib and alectinib, respectively. Among these, knocking down fibroblast growth factor receptor substrate 2 (FRS2) or coiled-coil and C2 domain–containing protein 1A (CC2D1A), both scaffolding proteins, sensitized multiple ALK fusion cell lines to the ALK inhibitors crizotinib and alectinib. Collectively, our data set provides a resource that enhances our understanding of signaling and drug resistance networks consequent to ALK fusions and identifies potential targets to improve the efficacy of ALK inhibitors in patients.

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