Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment

Abstract

Summary KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted and immunotherapies. Among the different PDAC subtypes, basal-like mesenchymal PDAC, which is driven by allelic imbalance, increased gene-dosage and subsequent high expression levels of oncogenic KRAS, shows the most aggressive phenotype and strongest therapy resistance. Here, we perform a systematic high-throughput combinatorial drug screen and identify a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib, which targets KRAS-directed oncogenic signaling in mesenchymal PDAC. This combinatorial treatment induces cell cycle arrest and cell death, and initiates a context-dependent remodeling of the immunosuppressive cancer cell secretome. Using a combination of single cell RNA sequencing, CRISPR screens and immunophenotyping, we show that this combination therapy promotes intra-tumor infiltration of cytotoxic and effector T cells, which sensitizes mesenchymal PDAC to PD-L1 immune checkpoint inhibition. Overall, our results open new avenues to target this aggressive and therapy-refractory mesenchymal PDAC subtype.

The Role of Immunotherapy in Pancreatic Cancer

“…This study demonstrated promising results and better outcomes when the PARP inhibitor was combined with ipilimumab (15.4% ORR and 59.6% 6-month PFS) compared to nivolumab (7.1% ORR and 20.6% six-month PFS). In addition, novel promising targets for pharmacologic inhibition, such as heat shock protein 90 and multi-kinases, have shown the potential to sensitize immune-cold PDACs to IO therapy in preclinical studies [ 84 , 85 ]. Early studies have also demonstrated that targeting CSF1R, the CCL2-CCR2 chemokine axis, and Bruton tyrosine kinases, among many other targets, may modulate the immune milieu and could theoretically enhance ICI efficacy [ 86 , 87 , 88 ].…”

The Network Zoo: a multilingual package for the inference and analysis of biological networks

“…CREB3LI has been reported to be activated in drug resistant cell lines [57] and GLI1 knockdown has been shown to increase sensitivity to Vemurafenib [44], an approved melanoma BRAF inhibitor. Collectively, the results from these analyses suggest a co-involvement of TFs associated with both drug resistance and cell state transition in invasive disease and highlight the promise of multi-kinase targeting [58].…”

Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression

“…Recently, it was shown treating this class of PDAC with a MEK (trametinib) inhibitor and the multi-kinase (nintedanib) inhibitor which inhibits mutant KRas signaling allowed the infiltration of cytotoxic and effector T cells, and the cells became sensitive to the immune checkpoint inhibitor PD-L1. The combined inhibitor treatment resulted in cell cycle arrest and cell death, remodeled the immunosuppressive cancer cell secretome, and sensitized the PDAC to immune checkpoint therapy [ 177 ].…”