Recent Anti-KRASG12D Therapies: A "Possible Impossibility" for Pancreatic Ductal Adenocarcinoma

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, able to thrive in a challenging tumor microenvironment. Current standard therapies, including surgery, radiation, chemotherapy, and chemoradiation, have shown a dismal survival prognosis, resulting in less than a year of life in the metastatic setting. Methods: The pressing need to find better therapeutic methods brought about the discovery of new targeted therapies against the infamous KRAS mutations, the major oncological drivers of PDAC. Results: The most common KRAS mutation is KRAS^G12D, which causes a conformational change in the protein that constitutively activates downstream signaling pathways driving cancer hallmarks. Novel anti-KRAS^G12D therapies have been developed for solid-organ tumors, including small compounds, pan-RAS inhibitors, protease inhibitors, chimeric T cell receptors, and therapeutic vaccines. Conclusions: This comprehensive review summarizes current knowledge on the biology of KRAS-driven PDAC, the latest therapeutic options that have been experimentally validated, and developments in ongoing clinical trials.

Keywords: KRASG12D; PDAC; targeted therapies; tumor microenvironment.

Figure 1

RAS mutational rates. cBioPortal analysis from 2188 pancreatic ductal adenocarcinoma, 4158 non-small cell lung cancer, and 74 colorectal cancer patients. (a) The distribution of KRAS, NRAS, and HRAS in these three cancer regions is summarized in the table. (b) The distribution of KRAS variants in PDAC is presented in the pie chart.

Figure 2

The KRASG12D therapies. The KRAS pathway and therapeutic anti-KRASG12D, vaccination, and CAR-T therapies are considered at the forefront of PDAC research. Abbreviations: EGFR—Epidermal Growth Factor Receptor, RTK—Receptor Tyrosine Kinase, GRB2—Growth Factor Receptor-Bound Protein 2, SOS—Son Of Sevenless, SHP2—Src Homology 2 Containing Protein Tyrosine Phosphatase 2, GDP—Guanosine Diphosphate, GTP—Guanosine Triphosphate, GAP—Guanosine Triphosphate Activating Protein, GEF—Guanine Nucleotide Exchange Factor, P—Phosphorus, KRAS—Kirsten Rat Sarcoma Virus, PI3K—Phosphatidylinositol-3Kinase, AKT—Protein Kinase B, mTOR—Mammalian Target Of Rapamycin, RAF—Rapidly Accelerated Fibrosarcoma, MEK—Mitogen-Activated Protein, ERK—Extracellular Signal-Regulated Kinase, RAL—RAS-Like Proto-Oncogene, NF-kB—Nuclear Factor Kappa B.