Abstract
Gain-of-function screens reveal the context-specific lethality of oncogenic pathway activation.
Major Finding: Gain-of-function screens reveal the context-specific lethality of oncogenic pathway activation.
Concept: Tumors driven by MAPK, PI3K, or WNT signaling can be vulnerable to further pathway activation.
Impact: This study proposes pathway hyperactivation as a class of potentially actionable cancer dependencies.
A common approach to precision medicine is to inhibit pathways that become activated by cancer driver mutations or that comprise selective vulnerabilities in tumors of a given genotype. While this paradigm has supported the development of many agents that inhibit critical pathways, an increasing number of studies have proposed that hyperactivation of oncogenic pathways may impair tumor growth in certain contexts. To examine whether conditional pathway activation might represent a therapeutic vulnerability that is broadly observed in cancer, Chang and colleagues analyzed lineage-specific mutual exclusivity relationships between gene pairs observed in human tumor databases and focused on MAPK, PI3K, and WNT as pathways that may potentially lead to negative selection when hyperactivated. Key nodes of these pathways were selected for overexpression in gain-of-function open reading frame screens in 488 barcoded cancer cell lines, with the goal of identifying biomarkers correlated with vulnerability to pathway activation. The MAPK pathway was activated via overexpression of EGFRExon19del, KRASG12V, BRAFV600E, MEK1-DD, or ERK2, and this led to significant loss of viability in BRAF-mutant cells. Notably, sensitivity to hyperactivation was most evident in cell lines with high baseline MAPK activity, as reflected by strong negative effects in BRAF-mutant cells, significant but lesser effects in RAS-mutant cells, and negligible effects in receptor tyrosine kinase–driven cells. Similarly, activation of the PI3K pathway via AKT1E17K overexpression revealed sensitivity to pathway hyperactivation in cells that harbored PIK3CA or PTEN mutations, with the strongest viability defects validated in PIK3CA/PTEN double-mutant uterine cancer cell lines. Surprisingly, activation of the WNT pathway via β-catenin overexpression decreased viability specifically in APC-mutant cells, and the negative growth effects of β-catenin overexpression or APC knockdown in APC-mutant colorectal cancer (CRC) cell lines and organoids in vitro, as well as in cell line–derived xenografts in vivo, suggested that APC-mutant CRC requires residual activity of the β-catenin destruction complex to fine-tune β-catenin levels. Together, these findings highlight pathway hyperactivation events as an emerging class of context-specific vulnerabilities with therapeutic implications.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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