Rationale for MYC imaging and targeting in pancreatic cancer

Abstract

The incidence and lethality of pancreatic ductal adenocarcinoma (PDAC) will continue to increase in the next decade. For most patients, chemotherapeutic combination therapies remain the standard of care. The development and successful implementation of precision oncology in other gastrointestinal tumor entities point to opportunities also for PDAC. Therefore, markers linked to specific therapeutic responses and important subgroups of the disease are needed. The MYC oncogene is a relevant driver in PDAC and is linked to drug resistance and sensitivity. Here, we update recent insights into MYC biology in PDAC, summarize the connections between MYC and drug responses, and point to an opportunity to image MYC non-invasively. In sum, we propose MYC-associated biology as a basis for the development of concepts for precision oncology in PDAC.

Keywords: MYC; Pancreatic cancer; Precision oncology; Targeted therapies.

Fig. 1

Targeting of MYC. Illustrated are options of direct or indirect MYC inhibition by pharmacological inhibitors or activators, respectively. Indirect inhibition is achieved by interfering with transcription, translation. The concept to target MYC by synthetic lethality in PDAC is shown. Direct inhibition by a synthetic OMOMYC peptide or possibly by PROTACs renders the MYC protein itself nonfunctional. SE Super enhancer, BRD Bromodomain proteins

Fig. 2

Imaging of MYC. A Scheme for non-invasive annotating the MYC status. The TFRC gene is a MYC target. The Transferrin receptor can be imaged with a radiotracer, here ⁸⁹Zr-labeled transferrin (TF) or ⁶⁸Ga-citrate, which binds transferrin (TF). Overexpression of MYC leads to increased TFRC expression and augmented PET signal. B MYC and control Input ChIP-Seq data of human PDAC cells (MiaPaCa-2) published by Bhattacharyya et al. 2020 [36], were analyzed for specific binding of MYC to the TFRC gene. In addition, the exon structure of the TFRC gene is depicted (black boxes). C A mRNA expression dataset of human PDAC were retrieved via the publication of Bailey et al. [22] and curated as described [52]. A gene set enrichment analysis (GSEA) of Hallmark signatures via the GeneTrial 3.0 platform [110] was conducted comparing PDACs with TFRC mRNA expression in the highest quartile (Q4) versus PDACs in the quartiles Q1, Q2, and Q3. Each dot represents a significant hallmark signature. The MYC HALLMARK (v1) signature is highlighted in red