Unveiling the resistance to therapies in pancreatic ductal adenocarcinoma

Abstract

Despite the ongoing advances in interventional strategies (surgery, chemotherapy, radiotherapy, and immunotherapy) for managing pancreatic ductal adenocarcinoma (PDAC), the development of therapy refractory phenotypes remains a significant challenge. Resistance to various therapeutic modalities in PDAC emanates from a combination of inherent and acquired factors and is attributable to cancer cell-intrinsic and -extrinsic mechanisms. The critical determinants of therapy resistance include oncogenic signaling and epigenetic modifications that drive cancer cell stemness and metabolic adaptations, CAF-mediated stromagenesis that results in ECM deposition altered mechanotransduction, and secretome and immune evasion. We reviewed the current understanding of these multifaceted mechanisms operating in the PDAC microenvironment, influencing the response to chemotherapy, radiotherapy, and immunotherapy regimens. We then describe how the lessons learned from these studies can guide us to discover novel therapeutic regimens to prevent, delay, or revert resistance and achieve durable clinical responses.

Keywords: KRAS; PDAC; Therapy resistance; chemotherapy; immunotherapy; radiotherapy; resistance; stroma.

Figure 1:. The mechanisms driven by tumor and its TME in attributing resistance against therapeutic regimens in PDAC.

A. The major phenomena contributing to therapy resistance include signaling dysregulation by receptor tyrosine kinases, growth factor receptors and their ligands, epigenetic modulation, stemness, DNA damage, ECM stiffening, stromal remodeling, and immune modulation. B. The molecules/pathways associated with resistance to different therapeutic regimens, including gemcitabine, KRASi, radiotherapy, and immunotherapy. The various factors associated with a particular phenomenon regulating resistance to each therapeutic regimen are indicated by different colored arrows.

Figure 2:. Mechanisms of chemoresistance in PDAC.

Schematic illustration of different pathways contributing to chemoresistance.

Figure 3:. Mechanotransduction-driven therapy resistance in PDAC.

Different mechanisms, including actomyosin contraction, ECM stiffening, stromal remodeling, and high IFP, contribute to therapy resistance in PDAC. Tension induced by oncogenic mutation KRAS^G12D leads to integrin receptor clustering, which in turn interacts with other tyrosine kinases such as FAK, Src, and ROCK and induces deregulated signaling pathways associated with actomyosin contraction and mechanosignaling. Furthermore, direct or indirect communications between growth factor receptors and various ECM proteins (Collagen, Laminin, HA) can augment actomyosin contractions, mechanosignaling, and ECM remodeling, enhancing IFP. The soluble factors released from the tumor or various components of TME, such as TGFβ, TG2, Laminin, and LPA, result in the activation of JAK/STAT3, WNT, EMT, and YAP pathways through the tumor cells. Together, these pathways can culminate in mechanotransduction (increase in IFP, ECM stiffening, and stromal remodeling) inside the tumor, making it less permissive to systemic therapeutic agents.

Figure 4:. Various classes of Immunotherapies in PDAC.

Therapeutic strategies exploiting immune components to target tumors and their microenvironment in PDAC. These approaches mainly include blocking immune checkpoints (ICI), improving antigen presentation (immune stimulatory), inhibiting anti-inflammatory cytokines, and increasing immunogenicity (Vaccines and oncolytic viruses). Targets being exploited for these therapies in clinical trials are mentioned in the figure.