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Expert Opinion on Emerging Drugs Volume 27, 2022 - Issue 3
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Review

Emerging kinase inhibitors for the treatment of pancreatic ductal adenocarcinoma

Udo RudloffRare Tumor Initiative, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USACorrespondence[email protected]
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Pages 345-368 | Received 06 Jun 2022, Accepted 06 Oct 2022, Published online: 03 Nov 2022

Figures & data

Table 1. Current treatment options with designated regulatory approval in pancreatic cancer.

Figure 1. Protein kinase inhibitors under development in pancreatic cancer. A. Schematic representation of key targets and pharmacological agents that inhibit EGFR-RAS-MAPK signaling proteins (left). Inhibition of SHP2 pro-tumoral role within different cell populations in the tumor microenvironment (right) reduces tumor-promoting signaling via disruption of cancer cell-stromal cell crosstalk. Investigational anti-RAS agents highlighted with * indicate isoform-specific RAS inhibitors targeting the KRASG12C mutational isoform. B. Illustration of near ubiquitous focal adhesion kinase (FAK) – Src kinase activation via multitude of receptor tyrosine kinases (left) or extracellular matrix macromolecules (right) and respective pharmacological inhibitors. A selection of downstream effector signaling of FAK – Src kinase signaling is shown. C. Protein kinases involved in double strand DNA repair with emerging small molecule inhibitors.

Figure 1. Protein kinase inhibitors under development in pancreatic cancer. A. Schematic representation of key targets and pharmacological agents that inhibit EGFR-RAS-MAPK signaling proteins (left). Inhibition of SHP2 pro-tumoral role within different cell populations in the tumor microenvironment (right) reduces tumor-promoting signaling via disruption of cancer cell-stromal cell crosstalk. Investigational anti-RAS agents highlighted with * indicate isoform-specific RAS inhibitors targeting the KRASG12C mutational isoform. B. Illustration of near ubiquitous focal adhesion kinase (FAK) – Src kinase activation via multitude of receptor tyrosine kinases (left) or extracellular matrix macromolecules (right) and respective pharmacological inhibitors. A selection of downstream effector signaling of FAK – Src kinase signaling is shown. C. Protein kinases involved in double strand DNA repair with emerging small molecule inhibitors.

Figure 2. Schematic cartoon depicting different classes of kinase inhibitors. Chemical space targeted by different classes of kinase inhibitors shown in Orange, N- and C-lobe and hinge region of protein kinase in blue. Type I inhibitors compete with ATP binding in the active state of targeted kinase, DFG motif is (shown in purple) directed toward ATP binding site (DFG-in). Type II inhibitors block ATP binding in the inactive state of the targeted kinase (DFG-out). Type III and IV are allosteric kinase inhibitors with binding within the ATP cleft (type III) or independent from the ATP binding site (type IV).

Figure 2. Schematic cartoon depicting different classes of kinase inhibitors. Chemical space targeted by different classes of kinase inhibitors shown in Orange, N- and C-lobe and hinge region of protein kinase in blue. Type I inhibitors compete with ATP binding in the active state of targeted kinase, DFG motif is (shown in purple) directed toward ATP binding site (DFG-in). Type II inhibitors block ATP binding in the inactive state of the targeted kinase (DFG-out). Type III and IV are allosteric kinase inhibitors with binding within the ATP cleft (type III) or independent from the ATP binding site (type IV).

Figure 3. Impact of stromal barrier of pancreas cancer on intratumoral drug distribution. Illustration of unique desmoplastic pancreatic cancer stroma impairing effective intratumoral diffusion (top) with macromolecules of extracellular matrix (bottom left) and cellular partitions of stromal cells (bottom middle) forming barriers for drugs to reach target cells (bottom right).

Figure 3. Impact of stromal barrier of pancreas cancer on intratumoral drug distribution. Illustration of unique desmoplastic pancreatic cancer stroma impairing effective intratumoral diffusion (top) with macromolecules of extracellular matrix (bottom left) and cellular partitions of stromal cells (bottom middle) forming barriers for drugs to reach target cells (bottom right).

Table 2. Reported outcomes of pancreatic cancer patients treated with protein kinase inhibitors administered as single agent or in combination.

Table 3. Emerging protein kinase inhibitors under investigation for pancreatic cancer.

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