Xiangdong Lyu
Assistant Professor
The University of Texas Health Science Center at Houston
McGovern Medical School
Center for Translational Cancer Research
Despite the increasing numbers of effective agents for treating cancers, drug resistance remains the major barrier to long-term disease control. Our research focuses on understanding the fundamental mechanisms driving cancer therapy resistance. Specifically, we aim to uncover how cancer cells sense stress from therapeutic interventions, respond, adapt, and communicate with the tumor microenvironment to ultimately survive drug treatment. Our long-term goal is to identify conceptual and effective targets to prevent and overcome these resistances. We primarily focus on resistance to targeted therapy targeting KRAS, which is the most frequently mutated oncogene in human cancers. While inhibitors targeting oncogenic KRASG12C have received FDA approval, resistance to these KRAS inhibitors is common. We discovered that proteostasis reprogramming – a cellular process that maintains protein homoestasis – is a key mechanism driving resistance to KRAS inhibitor (Science, 2023). Given that proteostasis is orchestrated by a complex network of nearly 3,000 genes involved in protein synthesis, folding, remodeling, and degradation, we will systematically dissect the mechanism driving the proteostasis reprogramming in response to KRAS inhibitor. This will not only provide deep insights into the cell biology of proteostasis, but also develop novel concepts or strategies to overcome resistance to KRAS inhibitors. We also investigate the mechanism driving resistance to chemotherapy, as conventional chemotherapy remains the main systemic treatment option for multiple cancer types including triple-negative breast cancer (TNBC). About half of TNBC patients treated with neoajuvant chemotherapy fail to achieve a pathologic complete response, and the residual cancer burden leads to a high risk of metastasis and mortality. We identified a cancer cell metabolism reprogramming in response to chemotherapy and is critical for residual TNBC cells survival. Ongoing efforts will elucidate mechanisms driving the metabolism reprograming and develop mechanism-based strategies to prevent recurrence.
Education & Training
PhD, Shanghai Institute for Biological Sciences, 2016