Abstract 3913: Genomic loss of UQCR11 creates therapeutic vulnerability in triple-negative breast cancer
Authors: Sharma Samantha , Yu Tao , Achreja Abhinav , Zhang Xinna , Nagrath Deepak , Lu Xiongbin 
Published: April 2023

Recurrent loss-of-function deletions are prevalent genomic alterations in tumors; nonetheless, these deletions occasionally create conditional therapeutic vulnerabilities in tumors. Our previous study used The Cancer Genome Atlas High-Grade Serous Ovarian Carcinoma (TCGA-HGSOC) dataset to identify the 19p13.3 locus as the most pervasive deletion in the high-grade serous ovarian carcinoma (HGSOC). Subsequently, the machine learning integrated-precision oncology platform identified that the loss of UQCR11, a gene located within the chromosome 19p13.3 locus, created a therapeutic collateral target, the MTHFD2. Furthermore, pharmacological inhibition of MTHFD2 in the UQCR11-deleted cells led to complete tumor remission in our in vivo mouse model (Nature metabolism, 2022). Encouraged by the promising anti-tumor effect of the MTHFD2 inhibitor, we extended our research to other tumor types. By analyzing the TGCA datasets, we found that UQCR11 deletion was a common occurrence among humans' most prevalent solid tumors, especially in pan breast and lung cancer. Within the pan breast cancer dataset, we found that over 50% of patients with triple-negative breast cancer (TNBC), the most difficult-to-treat breast cancer subtype in women, displayed either heterozygous or homozygous deletions in the UQCR11 gene. Moreover, the TGCA-TNBC dataset analysis revealed that the genomic copy loss of UQCR11 positively correlates with the deceased mRNA expression of the gene, bringing our interest to validate the collateral lethal targets in this breast cancer subtype. We first analyzed The Cancer Cell Line Encyclopedia (CCLE) database and further explored the correlation between the copy number alteration and mRNA expression of UQCR11 in several breast cancer cell lines. Then, we selected seven human TNBC cells with copy number neutral or deletion UQCR11 and validated the copy number and gene expression of UQCR11 and MTHFD2 using qPCR and western blot. We next treated these cells with a selective MTHFD2 inhibitor, DS18561882, and found that UQCR11-deleted cells showed a more favorable response than the UQCR11-intact cells. Finally, to test the therapeutic potential of targeting MTHFD2-null tumors in vivo, we generated isogenic mouse breast cancer cell lines using shRNA-mediated UQCR11 knockdown. Consistent with our previous findings, the MTHFD2 expression level was upregulated upon UQCR11 knockdown, suggesting a compensation function of MTHFD2 in UQCR11-deleted cells. Furthermore, the UQCR11 knocked-down cells showed better responses to MTHFD2 inhibitor treatment than the parental control cells. In summary, our study provides evidence that targeting MTHFD2 holds strong therapeutic potential in over 50% of the TNBC patients with UQCR11 deletion and highlights the broad efficacy of targeting MTHFD2 for individualized therapeutic strategy in different tumor types co-occurring with UQCR11 deletion.

Citation Format: Samantha Sharma, Tao Yu, Abhinav Achreja, Xinna Zhang, Deepak Nagrath, Xiongbin Lu. Genomic loss of UQCR11 creates therapeutic vulnerability in triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3913.