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

Oncogenic KRAS mutations are present in >90% of pancreatic ductal adenocarcinoma (PDAC), with KRASG12D being the most common. Mutant-selective KRASG12D inhibitors (KRASiG12D) have demonstrated promising initial clinical activity in KRASG12D-mutant PDAC. However, adaptive resistance to KRASi constrains efficacy in some tumor types, such as colorectal cancer, in which EGFR-mediated RAS-MAPK pathway reactivation can be targeted to improve response. Some studies have suggested a similar role for EGFR in PDAC, but the mechanisms of adaptive resistance to KRAS inhibition are unclear.

Mechanisms of adaptive resistance to KRASiG12D were investigated in a panel of KRASG12D-mutant PDAC models.

We observed receptor tyrosine kinase (RTK)-driven adaptive reactivation of RAS pathway signaling following KRASiG12D in PDAC models. EGFR was a primary driver of adaptive RAS-MAPK reactivation in some models but was limited to those with epithelial differentiation. Conversely, adaptive RAS-MAPK reactivation in models with mesenchymal differentiation was primarily driven by FGFR signaling. In clinical PDAC specimens from The Cancer Genome Atlas, EGFR and ERBB3 expression was highly correlated with the expression of epithelial markers, whereas the expression of FGFR1 and mesenchymal markers was correlated. Notably, a RAS(ON) multi-selective inhibitor, which inhibits both wild-type and mutant RAS, abrogated RAS-MAPK reactivation in combination with KRASi in both epithelial and mesenchymal models and led to more consistent antitumor activity compared with combinations of KRASi and EGFR blockade.

In PDAC, adaptive RAS-MAPK reactivation following KRASG12D inhibition can be mediated by different RTKs and influenced by cell state. Combinations of mutant-selective KRASi and RAS(ON) multi-selective inhibitors may represent a promising universal strategy to surmount adaptive resistance in patients with PDAC.