Core Viewpoint - Colorectal cancer (CRC) is a significant global health issue, being the third most common cancer and the second leading cause of cancer-related deaths, with nearly 2 million new cases and around 1 million deaths annually. The rising incidence among individuals under 50 years old highlights the urgency for effective treatment strategies [2][5]. Group 1: Research Findings - The study published in Cell Reports Medicine indicates that combining DR5-targeting antibody-drug conjugates (ADCs) with CDK inhibitors presents a promising treatment strategy for advanced colorectal cancer [3][10]. - DR5 expression is elevated in both microsatellite stable (MSS) and microsatellite instability-high (MSI-H) colorectal cancer, suggesting its potential as a clinical treatment target [5][7]. - The ADC Oba01, which targets DR5 and carries the microtubule inhibitor MMAE, has shown remarkable efficacy in various colorectal cancer models, regardless of their microsatellite status [5][6]. Group 2: Mechanism of Action - Functional multi-omics analysis revealed that the cell cycle pathway and CDK are critical synergistic targets for the antitumor activity of Oba01. The study demonstrated that Oba01 can work synergistically with the FDA-approved CDK inhibitor abemaciclib in relevant in vivo models [6][8]. - CDK inhibitors enhance the cytotoxic effects of Oba01 on tumor cells both in vitro and in vivo, reinforcing the potential of this combination therapy [8][10]. Group 3: Study Highlights - The research generated colorectal cancer PDX/PDX-like organoid models that retain the molecular characteristics of the original tumors [7]. - The study identified CDK as a synergistic target for Oba01 through RNA sequencing and proteomics [7][10]. - The combined targeting of DR5, microtubule assembly, and CDK may provide an effective treatment approach for MSS and MSI-H colorectal cancer patients expressing DR5 [10].