Discovery of new targets

Figure of Project Achilles

Project Achilles (A) Schematic of the Project Achilles screening pipeline based on RNAi or CRISPR-Cas9 (B) Lineages represented in the current Project Achilles dataset. (C) Dependencies of known and validated genetic and therapeutic paradigms.

Formation of pancreatic ductal adenocarcinoma (PDAC) is a multistep process that frequently involves mutational activation of KRAS, sequentially followed by loss of CDKN2A, TP53, and SMAD4 tumor suppressor genes. KRAS comprises a key signaling switch, which is locked in the constitutively active conformation. Pancreatic cancer cells continue to require KRAS for survival or proliferation.

Finding a target

While all attempts to directly target KRAS so far have been futile, there is hope that we may eventually be able to target KRAS with an inhibitor. For now, much effort has centered on blocking the downstream signaling pathways, for example, the MAPK pathway using MEK or ERK inhibitors.

While MEK inhibitors elicit a partial response in melanoma, they are ineffective in PDAC. We have performed large-scale screens to identify modifiers of MEK inhibitor sensitivity, since these modifiers may reveal effective combination therapies that will overcome inhibitor resistance. In lung cancer, we have shown that the combination of MEK and TBK1 inhibitor is an effective combination in pre-clinical models, and a clinical trial based on this principle is ongoing. We are exploring if this combination might also work in PDAC.

We are also interrogating novel PDAC vulnerabilities by performing RNAi or CRISPR-Cas9 based loss-of-function screens in cell lines or tumor organoids. Targets identified in vitro are first confirmed in multiple cell lines and subsequently validated in vivo using GEMMs or PDXs.

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