American Association for Cancer Research
21598290cd141211-sup-139359_2_supp_0_np4l8y.pdf (2.2 MB)

Supplementary Figures S1 - S8 from HER2 Activating Mutations Are Targets for Colorectal Cancer Treatment

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journal contribution
posted on 2023-04-03, 20:41 authored by Shyam M. Kavuri, Naveen Jain, Francesco Galimi, Francesca Cottino, Simonetta M. Leto, Giorgia Migliardi, Adam C. Searleman, Wei Shen, John Monsey, Livio Trusolino, Samuel A. Jacobs, Andrea Bertotti, Ron Bose

Supplementary Figure S1. Drug sensitivity of HER2 or KRAS mutations in soft agar colony formation assay. Supplementary Figure S2. NCI-H508 cell xenograft growth curves. Supplementary Figure S3. Neratinib sensitivity of KRAS WT and KRAS mutant colorectal cancer lines. Supplementary Figure S4. HER2 mutant PDX's are cetuximab resistant. Supplementary Figure S5. Immunohistochemistry on PDX M122. Supplementary Figure S6. Immunohistochemistry on PDX M051. Supplementary Figure S7. HER2 L866M is an activating mutation that confers cetuximab resistance. Supplementary Figure S8. HER2 S310F is more sensitive to trastuzumab than HER2 L866M.



The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutants are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors neratinib and afatinib. HER2 gene sequencing of 48 cetuximab-resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) wild-type (WT) colorectal cancer patient-derived xenografts (PDX) identified 4 PDXs with HER2 mutations. HER2-targeted therapies were tested on two PDXs. Treatment with a single HER2-targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2-mutated PDXs.Significance: HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines, and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy. These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer. Cancer Discov; 5(8); 832–41. ©2015 AACR.See related commentary by Pectasides and Bass, p. 799.This article is highlighted in the In This Issue feature, p. 783