Overcoming Adaptive Resistance to KRASG12D Blockade in Pancreatic Cancer through Vertical Pathway Inhibition.

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is driven by KRAS mutations, with KRASG12D being most common.
• Mutant-selective KRASG12D inhibitors (KRASiG12D) show initial clinical promise for PDAC.
• Adaptive resistance to KRAS inhibitors limits efficacy, with mechanisms in PDAC not fully understood.

Purpose of the Study:

• Investigate adaptive resistance mechanisms to KRASiG12D in PDAC.
• Identify key signaling pathways and receptor tyrosine kinases (RTKs) involved in resistance.
• Evaluate potential combination strategies to overcome resistance.

Main Methods:

• Utilized a panel of KRASG12D-mutant PDAC models.
• Analyzed RAS-MAPK pathway reactivation following KRASiG12D treatment.
• Correlated RTK expression with cell differentiation markers in clinical PDAC specimens (TCGA).

Main Results:

• Observed RTK-driven adaptive reactivation of RAS signaling post-KRASiG12D.
• EGFR mediated resistance in epithelial PDAC models; FGFR drove resistance in mesenchymal models.
• A multi-selective RAS inhibitor combined with KRASi abrogated reactivation and improved antitumor activity.

Conclusions:

• Adaptive RAS-MAPK reactivation in PDAC is RTK-dependent and influenced by cell state.
• Combinations of mutant-selective KRASi and multi-selective RAS inhibitors offer a potential strategy against adaptive resistance.
• This approach may improve outcomes for PDAC patients treated with KRAS inhibitors.