A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer

Abstract

Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as KRAS and overall genomic complexity. Here, we report a novel approach to developing a personalized therapy for a patient with treatment-resistant metastatic KRAS-mutant colorectal cancer. An extensive genomic analysis of the tumor’s genomic landscape identified nine key drivers. A transgenic model that altered orthologs of these nine genes in the Drosophila hindgut was developed; a robotics-based screen using this platform identified trametinib plus zoledronate as a candidate treatment combination. Treating the patient led to a significant response: Target and nontarget lesions displayed a strong partial response and remained stable for 11 months. By addressing a disease’s genomic complexity, this personalized approach may provide an alternative treatment option for recalcitrant disease such as KRAS-mutant colorectal cancer.

Two-Faced: Roles of JNK Signalling During Tumourigenesis in the Drosophila Model

“…Nonetheless, research into Drosophila JNK signalling has, does, and will continue to support our understanding of JNK signalling in humans but, as it relates to cancer progression, more research is clearly needed. With the advent of transgenic RNAi (reviewed in Perrimon et al, 2010) and, more recently, CRISPR/Cas9 technology in Drosophila (reviewed in Housden and Perrimon, 2016;Bier et al, 2018), the generation of more sophisticated models of human cancer in flies has been possible, which can be used for chemical screening for anti-cancer compounds Sonoshita and Cagan, 2017;Cagan et al, 2019), a process already achieving promising results (Bangi et al, 2016(Bangi et al, , 2019. Similar methodologies using Drosophila as avatars for specific human cancers could be applied specifically to investigate whether the JNK pathway is pro-or anti-tumourigenic in particular contexts, and how it might be targeted to be beneficial therapeutically.…”

The phylogenetic functional conservation ofDrosophilaSeven-In-Absentia (SINA) E3 ligase and its two human paralogs, SIAH1 and SIAH2, inDrosophilaeye development

“…SIAH is a major tumor vulnerability and the most downstream gatekeeper of the oncogenic RAS/EGFR/HER2 signal transduction cascade [28][29][30][31][32]. Hence, the mechanistic insights of SINA/SIAH function gained from Drosophila genetic and mutagenesis studies will be easily translational, clinically relevant, and directly applicable to human cancer biology [66][67][68][69][70][71][72][73][74]. As we design better SIAH inhibitors to effectively shut down RAS-dependent signaling transmission in vivo, we aim to use the Drosophila eye, PNS, and salivary gland development as a model system and a rapid drug screening platform to test lead compounds and validate the efficacy of the next-generation anti-SIAH-based anti-K-RAS targeted gene therapy.…”

Zebrafish Avatars towards Personalized Medicine—A Comparative Review between Avatar Models

“…Alternatively to PDXs, genetically engineered models can also be used as Avatars. Very recently, Bangi et al [137] used the fruit fly (Drosophila melanogaster) to create genetically engineered fly Avatars, which had the same mutations (oncogenes and tumor suppressors) as the patient's cancer (9 different mutations). This was a patient with terminal colon cancer who developed resistance to many therapies.…”

“…Trametinib together with zoledronate showed the most effective action and were applied to the patient. The combination resulted in the shrinkage of the patient's tumor, but after 11 months the patient developed resistance [137].…”