Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

Abstract

ObjectiveThis study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means to treat pancreatic cancer.DesignPatient-derived cell lines and xenograft models were used to define the response to CDK4/6 and MEK inhibition in the tumour compartment. Impacts relative to immunotherapy were performed using subcutaneous and orthotopic syngeneic models. Single-cell RNA sequencing and multispectral imaging were employed to delineate effects on the immunological milieu in the tumour microenvironment.ResultsWe found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumour progression. These effects were associated with stable cell-cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single-cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors.ConclusionsTogether, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumour and immune microenvironment. This combination-targeted treatment can promote robust tumour control in combination with immune checkpoint inhibitor therapy.

An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer

“…In addition to SCNAs, m6Ascore is also associated with more events of KRAS and TP53 mutation. Dual inhibition of KRAS and cell cycle pathways can overcome immune evasion [ 49 , 50 ]. Mutation induced tumor heterogeneity and clonal evolution leads to dynamic immune landscape in tumor tissue, which may mediate efficacy of immunotherapy [51] .…”

Immunomodulation by targeted anticancer agents

“…Moreover, CDK4/CDK6 inhibitors have been successfully combined with other targeted anticancer agents to achieve improved immunostimulation and superior efficacy. For instance, in preclinical models of KRAS proto-oncogene, GTPase (KRAS)-driven lung and pancreatic adenocarcinoma, the mitogen-activated protein kinase kinase 1 (MAP2K1, best known as MEK1) and MEK2 inhibitor trametinib synergizes with palbociclib at inducing a SASP-dependent vascular response that enables tumor infiltration by immune effector cells (Knudsen et al, 2020;Ruscetti et al, 2018Ruscetti et al, , 2020. This results in improved disease control (in the lung model, where infiltration is dominated by natural killer [NK] cells) or restored sensitivity to ICIs (in the pancreatic model, where infiltration is dominated by exhausted CD8 + cytotoxic T lymphocytes [CTLs]) (Knudsen et al, 2020;Ruscetti et al, 2018Ruscetti et al, , 2020.…”

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

“…The application of GDC-0623 (cobimetinib), a MEK inhibitor, with an anti-CD40 antibody in murine models produced striking synergistic effects [69]. A strategy targeting both MEK and CDK4/6 not only delays tumour progression but also increases T-cell infiltration and tumour sensitivity to immune checkpoint inhibitors in xenograft models [70]. Interestingly, in breast cancer, the combined application of trametinib and rosiglitazone transforms cancer cells into adipocytes.…”

“…For instance, CDK4/6 inhibitors block the DNA repair machinery, increasing the sensitivity of PDAC cells to PARP inhibitors [113]. In addition, the combined inhibition of CDK4/6 and MEK modulates the PDAC microenvironment, increasing the sensitivity of PDAC cells to immune checkpoint blockade [70]. The application of abemaciclib and YAP1 or HuR inhibitors also exerts a synergistic inhibitory effect on PDAC cell lines [114].…”