Pancreatic cancer (KEGG map)

Infiltrating ductal adenocarcinoma is the most common pancreatic malignancy and progresses from normal duct epithelium through histologically defined precursors (PanINs). KEGG map hsa05212 draws the sequence: HER2 (ERBB2) over-expression and activating KRAS point mutation occur early, inactivation of p16 (CDKN2A) at an intermediate stage, and inactivation of TP53, SMAD4 and BRCA2 relatively late. Activated KRAS engages several effector arms at once: RAF-MEK-ERK, PI3K-AKT and RalGDS. EGFR family receptors sit both upstream of RAS and downstream of it, because RAS induces autocrine EGFR ligands; HER2 also feeds JAK-STAT. Loss of p16 releases CDK4/6 and the G1/S checkpoint; loss of TP53 removes damage-induced arrest; loss of SMAD4 removes the growth-inhibitory arm of TGF-beta signalling. The tumours show extensive genomic instability and aneuploidy, to which telomere attrition and TP53 and BRCA2 mutation contribute.

Kleeff and colleagues, Nature Reviews Disease Primers, 2016 (doi:10.1038/nrdp.2016.22) review the disease: KRAS mutation is found in more than 90 percent of tumours, CDKN2A, TP53 and SMAD4 are the other frequently altered drivers, a dense stroma limits drug delivery, and germline BRCA1/2 and other homologous recombination defects define a subset that responds to platinum and PARP inhibition.

What drugs do about it: direct KRAS inhibition has arrived, with KRAS G12C inhibitors (sotorasib, adagrasib) for the small G12C subset and the pan-RAS(ON) inhibitor daraxonrasib in phase 3 for the common G12D and G12V mutations; olaparib maintenance treats germline BRCA-mutant disease after platinum; erlotinib with gemcitabine (listed by KEGG) gives a small EGFR-directed benefit; larotrectinib and entrectinib treat rare NTRK fusion tumours; pembrolizumab treats the rare MSI-high tumours. Cytotoxic chemotherapy (FOLFIRINOX, gemcitabine with nab-paclitaxel) remains the backbone.