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FB2026_01
,
released March 12, 2026
Activating mutations in one of the human RAS genes (KRAS, NRAS, and HRAS) are present in up to half of colorectal cancers, but therapeutic options for targeting RAS-dependent cancers are limited. A personalized multigenic Drosophila model was used to identify possible therapeutic options for a patient with treatment-resistant metastatic KRAS-mutant colorectal cancer.
An extensive genomic analysis of the tumor identified nine key drivers. A transgenic model that altered orthologs of these nine genes in the Drosophila hindgut was developed: an activated form of Dmel\Ras85D (orthologous to human KRAS), and RNAi directed against eight genes: Dmel\Apc (orthologous to human APC); Dmel\p53 (orthologous to human TP53); Dmel\ago (orthologous to human FBXW7); Dmel\put (orthologous to human TGFBR2); Dmel\brm (orthologous to human SMARCA4); Dmel\ft (orthologous to human FAT4); Dmel\p38a (orthologous to human MAPK14); Dmel\shg (related to human CDH1). Targeting transgene expression to the developing hindgut epithelium can lead to broad transformation in the epithelium and organismal lethality; this lethality can be rescued by drugs mixed with the fly food. A robotics-based screen using this platform identified a candidate treatment combination; corresponding treatment of the patient led to a partial, but significant, response.
[updated Nov. 2019 by FlyBase; FBrf0222196]
Mutations in one of the human RAS genes are present in a large proportion of colorectal cancers: an estimated 30 to 50% of CRC patient tumors include an oncogenic KRAS mutation; an additional ~6% of colorectal tumors contain mutations in NRAS or HRAS; however, therapeutic options for targeting RAS-dependent cancers are limited (FBrf0242473 and references cited therein).
High-scoring ortholog of human genes KRAS, HRAS, and NRAS (many to many; multiple paralogs and orthologs in both species). Dmel\Ras85D shares 78-86% identity and 86-92% similarity with KRAS, HRAS, and NRAS; for these three human genes, Ras85D is the highest-scoring ortholog in Drosophila.
Ortholog of human genes APC and APC2 (2 Drosophila to 2 human). Dmel\Apc shares 25-26% identity and 37% similarity with both human genes; it lacks a microtubule-binding domain found at the C terminus of the human APC gene.
High-scoring ortholog of human genes TP53, TP63 and TP73 (1 Drosophila to many human). Dmel\p53 shares 20-24% identity and 36-41% similarity with the human genes.
Moderate-scoring ortholog of human FBXW7 (1 Drosophila to 1 human). Dmel\ago shares 58% identity and 67% similarity with the human gene.
High-scoring ortholog of human ACVR2B and ACVR2A; low-scoring ortholog of human TGFBR2 (multiple genes in both species). Dmel\put shares 47-48% identity and 63% similarity with ACVR2B and ACVR2A; it shares 32% identity and 51% similarity with TGFBR2.
High-scoring ortholog of human SMARCA2 and SMARCA4 (1 Drosophila to 2 human). Dmel\brm shares 50-51% identity and 62-63% similarity with the human genes.
High-scoring ortholog of human FAT4 (1 Drosophila to 1 human). Dmel\ft shares 36% identity and 53% similarity with the human gene.
High-scoring ortholog of human MAPK14 (multiple genes in both species). Dmel\p38a shares 70% identity and 80% similarity with the human MAPK14 gene.
Low-scoring ortholog of human type II cadherin CDH20 (most closely related) and multiple others (many Drosophila to many human), including CDH1. Dmel\shg shares 19% identity and 29% similarity with human CDH20.