Abstract 4980: Altered Pan-Ras Pathway and Activating Mutations in EGFR Result in Elevated CD73 in Multiple Cancers

Background: Adenosine production mediated by CD73 and/or TNAP is a potential mechanism of immune suppression across many cancer types. We have previously shown that AB928, a dual A2aR/A2bR antagonist, in combination with anti-PD-1 or chemotherapy, rescues the immunosuppressive effects of adenosine in experimental tumor models. Oncogene-driven cancers are targeted with specific tyrosine kinase inhibitors, typically leading to the development of several resistance mechanisms that bypass the kinase signaling. These oncogene-driven cancers tend to be non-responsive to PD(L)-1 inhibition. We hypothesized that oncogenic drivers might be regulating adenosine production machinery as a mechanism to suppress and evade the immune system. Here we show that pan-RAS, BRAF and EGFR alterations drive the expression of CD73, which may contribute to suppressed anti-tumor immunity. Methods and Results: We used linear models to evaluate the ability of 299 pan-cancer consensus oncogenic drivers (Bailey et al, 2018) to predict CD73 expression independent of tumor type in PanCanAtlas TCGA dataset. We defined a given gene as either wild type or altered if it exhibited a SNV/copy number/fusion event in a given patient. Out of the 299 oncogenes, we identified 20 oncogenes that upregulated and 26 that downregulated CD73 expression (FDR < 0.05). Alterations in KRAS, BRAF and EGFR were the top 3 oncogenes upregulating CD73 expression, followed by other kinases such as RASA1, MET, RET, SMAD4 and CDK4. In KRAS/BRAF/EGFR altered tumors, CD73 expression was significantly higher compared to respective wild-type patients in all cancers combined, as well as in individual tumor types (BRCA, LUAD, LUSC, CRC, PAAD, HNSCC, UBC, CESC, ESCA, STAD, UCEC and LGG). Furthermore, the pan-cancer Ras activation classifier score (Way et.al 2018) was highly predictive of CD73 expression independent of tumor type (p-value < 2e-16). KRAS, HRAS, BRAF, EGFR as well as pan-Ras mutant cancer cell lines exhibited a significantly higher level of CD73 expression than wild-type cell lines, independent of cancer type. Conclusions: Activating mutations in KRAS and HRAS that result in deregulation of the Ras pathway serve as oncogenic drivers in a variety of cancer types such as CRC, NSCLC, gastric-esophageal, cervical, bladder and HNSCC and upregulate CD73. BRAF mutations are enriched in breast, CRC, NSCLC, and low-grade gliomas that exhibit higher CD73 expression. Finally, EGFR mutations are prominent in RCC, low-grade gliomas and NSCLC, which drive CD73 expression. Oncogene-driven cancers are largely unresponsive to PD-(L)1 inhibition and are targeted with kinase inhibitors resulting in significant but not durable clinical responses. Our data strongly suggests that CD73 inhibition with AB680 and/or A2R antagonism with AB928 might be effective in Ras pathway mutant and EGFR mutant cancers, either in TKI-naïve or relapsed settings. Citation Format: Akshata R. Udyavar, Daniel DiRenzo, Devika Ashok, Amy E. Anderson, Stephen W. Young, Matt J. Walters, Joanne Bl Tan. Altered pan-Ras pathway and activating mutations in EGFR result in elevated CD73 in multiple cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4980.