IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies

Abstract

Among patients with colorectal cancer who benefit from therapy targeted to the epidermal growth factor receptor (EGFR), stable disease (SD) occurs more frequently than massive regressions. Exploring the mechanisms of this incomplete sensitivity to devise more efficacious treatments will likely improve patients' outcomes. We tested therapies tailored around hypothesis-generating molecular features in patient-derived xenografts ("xenopatients"), which originated from 125 independent samples that did not harbor established resistance-conferring mutations. Samples from xenopatients that responded to cetuximab, an anti-EGFR agent, with disease stabilization displayed high levels of EGFR family ligands and receptors, indicating high EGFR pathway activity. Five of 21 SD models (23.8%) characterized by particularly high expression of EGFR and EGFR family members regressed after intensified EGFR blockade by cetuximab and a small-molecule inhibitor. In addition, a subset of cases in which enhanced EGFR inhibition was unproductive (6 of 16, 37.5%) exhibited marked overexpression of insulin-like growth factor 2 (IGF2). Enrichment of IGF2 overexpressors among cases with SD was demonstrated in the entire xenopatient collection and was confirmed in patients by mining clinical gene expression data sets. In functional studies, IGF2 overproduction attenuated the efficacy of cetuximab. Conversely, interception of IGF2-dependent signaling in IGF2-overexpressing xenopatients potentiated the effects of cetuximab. The clinical implementation of IGF inhibitors awaits reliable predictors of response, but the results of this study suggest rational combination therapies for colorectal cancer and provide evidence for IGF2 as a biomarker of reduced tumor sensitivity to anti-EGFR therapy and a determinant of response to combined IGF2/EGFR targeting.

Interrogating open issues in cancer precision medicine with patient-derived xenografts

“…In all these studies, responses obtained in mice were highly consistent with responses in patients. For example, the distribution of tumour regression, disease stabilization and progression in colorectal cancer xenopatients receiving EGFR antibodies was similar to that found in the clinic, and treatment-refractory tumour grafts were enriched for known genetic predictors of therapeutic resistance in patients 6 (TABLE 3); moreover, in analogy with clinical studies 120 , the addition of an EGFR smallmolecule inhibitor to the EGFR antibody increased tumour regression 118 .…”

“…Through this effort, several genetic determinants of resistance to EGFR blockade were discovered, including amplifications or mutations in genes encoding druggable kinases 6,7,115,116 . Similarly, more dynamic features such as expression changes in pro-survival genes and the activation of compensatory feedback loops during treatment were identified as mechanisms of tumour adaptation to EGFR family 117,118 or MEK 119 inhibition in colorectal cancer. The flexibility of PDXs also enabled preclinical testing of drug combinations in models displaying some of these resistance traits, with a permutation capability that was clearly beyond the number of testable hypotheses in humans (FIG.…”

Cetuximab Resistance in Squamous Carcinomas of the Upper Aerodigestive Tract Is Driven by Receptor Tyrosine Kinase Plasticity: Potential for mAb Mixtures

“…In models of lung cancer, increased IGF1R activation was shown to mediate chromatin modifications that confer a reversible state of "drug tolerance" to gefitinib (53). Recently, IGF2 was shown to limit the response to cetuximab in models of colorectal cancer and synergistic activity of cetuximab, and a small molecule inhibitor of IGF1R was demonstrated (54).…”

Molecular Markers of Sensitivity and Resistance of Colorectal Cancer to Anti-Egfr Therapy

“…Эти сведения не со-гласуются с наблюдениями, полученными в ходе лабораторных экспериментов [19]. Возможно, не-гативной предиктивной ролью обладает экспрессия IGF2, который взаимодействует с рецепторной тирозинкиназой IGF1R, последняя, подобно EGFR, способна запускать онкогенные сигнальные каска-ды PI3K/Akt и RAS-MAPK [54].…”