Targeted EGFR for basal subtype pancreatic cancer

Abstract public domain (NIH RePORTER)

Abstract We and others have shown that basal tumors, which comprise <20% of PDAC tumors, are resistant to the first- line chemotherapy regimen FOLFIRINOX. We show that basal tumors are significantly enriched in receptor tyrosine kinases, including EGFR. While EGFR inhibitors have been consistently disappointing in PDAC, our analysis of two clinical trials where patients were treated with gemcitabine in combination with an EGFR inhibitor, shows that the negative results are very likely driven by the previous lack of knowledge of subtypes. In both clinical trials, patients with basal tumors significantly benefit from EGFR inhibitor treatment. It is noteworthy that the survival of patients with basal subtype tumors is significantly worse than patients with classical tumors. We show that, for the very first time, basal patients who receive anti-EGFR therapy benefit from EGFR inhibitor therapy (patients with classical subtype tumors do not), and can achieve equivalent outcome to classical patients. Our findings strongly support that the positive subgroup analysis of basal patients is explained by the higher EGFR kinase expression found in basal tumors. These data strongly support our hypothesis that targeting subtype-specific kinases will be key to promising precision oncology approaches for kinase inhibitors in PDAC. We propose a multi-disciplinary team of a translational researcher (Yeh), kinome expert (Johnson), and medical oncologist (Somasundaram), that takes the next step in determining if EGFR inhibitors should be repurposed for patients with basal subtype tumors, and leverages a transformative high sensitivity method of defining the kinome in low input samples such as biopsies, to identify targeted approaches specifically for basal subtype tumors.

Public health relevance public domain (NIH RePORTER)

Narrative We and others have shown that basal tumors, which comprise <20% of PDAC tumors, are resistant to the first- line chemotherapy regimen FOLFIRINOX. We leverage a transformative high sensitivity method of defining the kinome in low input samples such as biopsies, to identify targeted approaches specifically for basal subtype tumors.