Initiation of pancreatic ductal adenocarcinoma (PDAC) is driven by oncogenic KRAS mutation, and disease progression is associated with frequent loss of tumor suppressors.
Inactivating mutations in tumor suppressor genes such as CDKN2A/p16, TP53, and SMAD4 cooperate with KRAS mutations to cause aggressive PDAC tumor growth.
We used droplet digital polymerase chain reaction (ddPCR) to detect the expression of KRAS-mutated genes in plasma samples of 65 PDAC patients who underwent IRE.
However, in pancreatic ductal adenocarcinoma (PDAC) there are only four abundantly common driver mutations (KRAS, CDKN2A, TP53, and SMAD4), which are not currently actionable.
In explant cells derived from these PDX tumor models with a KRASG12R mutation, treatment with inhibitors of CDKs (including CDK9) reduced phosphorylation of a marker of CDK9 activity (phospho-RNAPII CTD Ser2/5) and reduced viability/growth of explant cells derived from PDAC PDX models.
We developed an approach to statistically humanize the mouse networks with data from human cancer and identified genes within the humanized CRC and PDAC networks synthetically lethal with mutant KRAS.
In pancreatic ductal adenocarcinoma (PDAC), mutant KRAS stimulates the translation initiation factor eIF5A and upregulates the focal adhesion kinase PEAK1, which transmits integrin and growth factor signals mediated by the tumor microenvironment.
While CDK4/6 represents a downstream target of both KRAS mutation and loss of the CDKN2A tumor suppressor in PDAC, clinical and preclinical studies indicate that pharmacological CDK4/6 inhibitors are only modestly effective.
Circulating cell-free DNA (cfDNA) is a promising resource to detect molecular characteristics of tumors, supporting the concept of "liquid biopsy".We determined the mutational status of KRAS in plasma cfDNA using multiplex droplet digital PCR in 259 patients with PDAC, retrospectively.
As demonstrated by either cytology or finding of a KRAS mutation, CTC were detected in 18 of 21 patients (86 %) with proven PDAC: 8 out of 10 patients (80 %) with early stage (UICC IIA/IIB) and 10 out of 11 (91 %) with late stage (UICC III/IV) disease.
Pancreatic juice from PDAC patients is rich in KRAS mutations often not seen in the primary tumor and possibly reflecting precancerous lesions in other regions of the pancreas.
The authors also discuss other targets relevant to PDAC including those downstream of mutated KRas, such as MAPK kinase and phosphatidylinositol 3-kinase.
KRAS mutations are present in >90% of PDAC and are connected to many signaling pathways through its oncogenic cascade, including extracellular regulated kinase (ERK) and MYC.
In summary, we conclude that albumin conjugation is an exploitable drug delivery strategy that significantly opens the therapeutic windows of otherwise undevelopable anti-cancer agents for KRAS-mutant PDAC therapy, and creates a new landscape for clinical evaluation and future translation of such compounds.