Abstract PR01: Acquisition of resistance to anti-EGFR therapy drives genomic heterogeneity and lesion-specific responses in colorectal cancer

Media type: E-Article

Title: Abstract PR01: Acquisition of resistance to anti-EGFR therapy drives genomic heterogeneity and lesion-specific responses in colorectal cancer

Contributor: Siravegna, Giulia; Russo, Mariangela; Blaszkowsky, Lawrence S.; Corti, Giorgio; Crisafulli, Giovanni; Ahronian, Leanne G.; Mussolin, Benedetta; Kwak, Eunice L.; Buscarino, Michela; Lazzari, Luca; Valtorta, Emanuele; Truini, Mauro; Jessop, Nicholas A.; Robinson, Hayley E.; Hong, Theodore S.; Mino-Kenudson, Mari; Di Nicolantonio, Federica; Thabet, Ashraf; Sartore-Bianchi, Andrea; Siena, Salvatore; Iafrate, John; Corcoran, Ryan B.; Bardelli, Alberto

imprint: American Association for Cancer Research (AACR), 2015

Language: English

DOI: 10.1158/1535-7163.targ-15-pr01

ISSN: 1535-7163; 1538-8514

Keywords: Cancer Research ; Oncology

Origination:

Footnote:

Description: Abstract How genomic heterogeneity associated with acquired resistance to targeted agents affects response to subsequent lines of therapy is unknown. Exposure to therapy may result in selection of sub-clonal cell populations, capable of growing under drug pressures. Therefore, a single-lesion biopsy at disease progression may vastly underrepresent the molecular heterogeneity of resistant tumor clones in an individual patient and may fail to detect the existence of distinct but important resistance mechanisms that could impact clinical response. To this aim, we identified a colorectal cancer (CRC) patient in whom multiple tumor biopsies were obtained at resistance following prolonged response to with the anti-EGFR antibody cetuximab and irinotecan therapy. Full-exome sequencing of 1000 cancer genes of both primary tumor and progression biopsy revealed a TP53 mutation in all samples and a novel MAP2K1 p.K57T mutation in one of the progressing liver biopsy. Interestingly, a mutation at the same MAP2K1 codon was identified in the cetuximab-resistant HCA46 CRC cell line. Biochemical analysis of preclinical model showed constitutive activation of MEK and ERK despite cetuximab treatment. Exogenous expression of the same mutant MEK1, but not wild-type MEK1, in an independent RAS-WT CRC cell line, LIM1215, conferred resistance to cetuximab or panitumumab. However, the combination of the MEK inhibitor trametinib with either cetuximab or panitumumab restored sensitivity, suggesting a potential therapeutic strategy to overcome resistance to EGFR blockade caused by this mutation. Accordingly, the patient was treated with the combination of panitumumab and trametinib. After 3 months, imaging demonstrated a reduction in size of the biopsied liver metastasis harboring the MAP2K1 mutation, but revealed that some other lesions had progressed. Plasma for circulating DNA (ctDNA) analysis was longitudinally collected during combinatorial treatment. Pre-treatment plasma was analyzed using next-generation sequencing (NGS), confirming the presence of both TP53 and MAP2K1 variants, but surprisingly unveiling an additional KRAS mutation. ddPCR analysis of longitudinal timepopints of ctDNA unveiled that TP53 mutant levels dropped after initiation of therapy, but rose later during treatment with concomitantly/in parallel to CEA ones. However, MAP2K1 mutant levels declined, while KRAS mutant ones rose markedly during therapy, indicating outgrowth of a resistant KRAS-mutant clone. Biopsy of a different liver metastasis' segment that progressed despite panitumumab and trametinib revealed the same KRAS mutation identified in ctDNA. In summary these findings illustrate how individual metastatic lesions can develop distinct resistance mechanisms to targeted agents, leading to striking differences in lesion-specific response to subsequent targeted therapies. As more trials evaluating targeted therapy strategies designed to overcome specific acquired resistance mechanisms enter the clinic, genomic results from single-tumor biopsies should be interpreted with caution. By contrast, liquid biopsy approaches have the potential to detect the presence of simultaneous resistance mechanisms residing in separate metastases in a single patient and to monitor the effects of subsequent targeted therapies. Citation Format: Giulia Siravegna, Mariangela Russo, Lawrence S. Blaszkowsky, Giorgio Corti, Giovanni Crisafulli, Leanne G. Ahronian, Benedetta Mussolin, Eunice L. Kwak, Michela Buscarino, Luca Lazzari, Emanuele Valtorta, Mauro Truini, Nicholas A. Jessop, Hayley E. Robinson, Theodore S. Hong, Mari Mino-Kenudson, Federica Di Nicolantonio, Ashraf Thabet, Andrea Sartore-Bianchi, Salvatore Siena, John Iafrate, Ryan B. Corcoran, Alberto Bardelli. Acquisition of resistance to anti-EGFR therapy drives genomic heterogeneity and lesion-specific responses in colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR01.

Access State: Open Access

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