Xi Chen
Regular Member
Associate Professor
The University of Texas MD Anderson Cancer Center at Houston
Department of Experimental Therapeutics
Xi Chen laboratory studies how cancer and its immune microenvironment sense and respond to stresses and therapeutic insults to evade immune surveillance and develop drug resistance. I have broad backgrounds in cancer stress biology, immunology, Endoplasmic Reticulum (ER) stress, Unfolded Protein Response (UPR), protein quality control, genomics, transgenic and preclinical animal models, and stem cell biology. My laboratory’s research focuses on three major directions:
- Stress Responses in Therapy Resistance and Immunosuppression. Resistance to chemotherapy and immunosuppression in the tumor microenvironment are major clinical challenges that account for cancer patient mortality and unresponsiveness to cancer immunotherapy. My group identified the ER stress signaling as a major mediator of chemotherapy resistance and immunosuppression in solid tumors (JCI, 2018; Nature Reviews Cancer, 2020; Cell, 2024). We were the first to discover IRE1α/XBP1 branch of the UPR as a synthetic lethal partner of MYC and a key regulator of breast cancer resistance to chemotherapy (JCI, 2018. citation: >140). We found that the ER stress sensor IRE1α is frequently co-amplified with MYC in breast cancer. MYC hijacks IRE1α/XBP1 UPR pathway to alleviate proteotoxic stress and sustain tumor progression. MYC is synthetic lethal with IRE1α/XBP1 inhibition. Genetic or pharmacological suppression of IRE1α/XBP1 pathway selectively inhibits MYC-driven tumor progression without toxicity to normal tissues. Importantly, we characterized an IRE1α inhibitor ORIN1001 that selectively suppresses IRE1α RNase activity and substantially sensitizes the MYC-driven breast tumors to docetaxel chemotherapy. Combination therapy with ORIN1001 and docetaxel leads to rapid tumor regression of MYChigh breast tumors (JCI, 2018). Furthermore, our recent study identified IRE1α as an innate immune checkpoint to restrict chemotherapy-induced pore-forming pyroptosis (Cell, 2024). IRE1α RNase inhibitor plus taxane converts PD-L1-negative “cold” triple-negative breast tumors, which are unresponsive to immune checkpoint inhibitor at all, into PD-L1–high “hot” tumors that are hyper-sensitive to PD-1 inhibitor. My group’s studies imply that targeting this ER stress response pathway offers a novel and effective treatment strategy for breast cancer patients. These studies led to the first-in-human clinical trial of IRE1α inhibitor ORIN1001 and received FDA Fast Track designation status.
- Proteostasis Reprogramming in Therapy Resistance. Most cancers are addicted to a balanced protein homeostasis (proteostasis) network to maintain oncogenic growth, and therapeutic insults often disrupt proteostasis and induce proteotoxic stresses. Residual drug-tolerant cells must overcome imbalances in the proteostasis network to maintain survival. However, how proteostasis network is orchestrated by driver oncogenes and the proteostasis reprogramming mechanisms that bypass oncogene addiction and allow for acquired resistance to targeted therapies remain largely unknown. My group is the first to discover the proteostasis reprogramming mechanisms that bypasses oncogene addiction and promote therapy resistance (Science, 2023). We found that oncogenic KRAS is critical for protein quality control in tumor cells. Inhibition of oncogenic KRAS rapidly inactivates both cytosolic and endoplasmic reticulum (ER) protein quality control machinery, two essential components of the proteostasis network, via inhibiting the master regulators HSF1 and IRE1α. However, residue cancer cells that survive KRAS inhibitor (KRASi) directly re-activate IRE1α through an ER stress-independent unconventional phosphorylation mechanism that re-establishes proteostasis and sustains acquired resistance to KRAS inhibition. Importantly, we show that IRE1α is the convergence point of multiple resistance mechanisms in KRASi-resistant tumors. Genetic or pharmacological suppression of IRE1α collapsed the re-established proteostasis network and overcame resistance to KRASi sotorasib, leading to complete and durable responses in most non-small cell lung cancer (NSCLC) PDX models. Despite the FDA approval of KRASG12C inhibitors sotorasib and adagrasib for treating KRASG12C-mutant NSCLC, adaptive resistance to these inhibitors is rapid and almost inevitable, thus representing a major clinical challenge. Our study directly addressed this challenge by revealing proteostasis reprogramming as a convergence point of multiple resistance mechanisms to KRAS inhibitor that can be therapeutically targeted.
- Stress Responses and Protein Quality Control in Hematopoiesis, Adaptive Immunity, and Aging. Another research area of my group focuses on stress responses in hematopoiesis, immunity and microenvironment. Stem cells need to be protected from genotoxic and proteotoxic stress to maintain a healthy pool throughout life. However, little is known about the proteostasis mechanisms that safeguard stem cells. We were the first to identify ER-Associated Degradation (ERAD) as a protein quality checkpoint that controls the hematopoietic stem cell (HSC)-niche interaction and determines HSC fate (Nature Cell Biology, 2020). We found that HSCs exhibit low levels of protein synthesis, but employ highly robust protein quality control via ERAD to prevent misfolded protein aggregation and ensure the efficient maturation of surface receptors to ultimately safeguard the stem cell pool by regulating the stem cell-niche interactions. This essential proteostasis mechanism could be targeted to enhance stem cell function, especially in aging process. Furthermore, we discovered a critical function of ERAD in selectively regulating ab T cell development in the thymus (eLife, 2021). Importantly, we found that enhancing ERAD activity substantially promotes T cell generation that could potentially be targeted to improve adaptive immunity during the aging process. Declining adaptive immunity with age contributes to the increased incidence of cancer due to the compromised immune surveillance. Loss of HSC self-renewal and thymus involution are major causes of declined adaptive immunity. Our studies identify ERAD as an essential proteostasis mechanism sustaining HSC identity and T cell development. Importantly, our preliminary data show that ERAD-KO mice exhibit HSC- and thymus- aging phenotypes. Enforced activation of key ERAD components significantly improve T cell development and adaptive immunity.
In summary, my lab’s mechanism-driven highly translational research has immediate clinical impact, the long-term goals of my group are to elucidate the significance and mechanisms of stress responses and proteostasis in therapy resistance and anti-tumor immunity; and to revolutionize the treatment regimens for immune-cold cancers as well as overcoming therapy resistance to transform cancer to a manageable chronic disease.
Education & Training
PhD, National University of Singapore, 2009