Abstract B229: Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer
Authors: Bardelli Alberto , Bianchi Andrea Sartore , Di Nicolantonio Federica , Nichelatti Michele , Molinari Francesca , De Dosso Sara , Saletti Piercarlo , Martini Miriam , Sarnataro Carolina , Pozzi Federico , Mazzucchelli Luca , Lamba Simona , Veronese Silvio , Frattini Milo , Siena Salvatore 
Published: June 2012

Abstract
Personalized cancer medicine based on the genetic milieu of individual tumors has long been postulated but until recently this concept was not supported by clinical evidence. The advent of the EGFR-targeted monoclonal antibodies cetuximab and panitumumab has revolutionized the therapy of colorectal tumors and paved the way to the individualized treatment of this cancer type. From the initial observation that cetuximab or panitumumab as monotherapy are effective only in 10–20%, of mCRCs, knowledge has being gained on the molecular mechanisms underlying primary resistance to these agents. It has already been unequivocally established that KRAS mutations, which occur in 35–45% of colorectal cancers, preclude responsiveness to EGFR-targeted therapy. However, less than 20% patients displaying wild-type KRAS tumors achieve objective response. Alterations in other effectors downstream of the EGFR, such as BRAF, and deregulation of the PIK3CA/PTEN pathway have independently been suggested to give rise to resistance.
Molecular profiling of tumor samples and functional analysis of cellular models were preformed to clarify the relative contribution of molecular alterations to resistance. We retrospectively analyzed objective tumor response, progression-free (PFS) and overall survival (OS) together with the mutational status of KRAS, BRAF, PIK3CA and expression of PTEN in 132 tumors from cetuximab or panitumumab treated mCRC patients. Among the 106 non responsive patients, 74 (70%) had tumors with at least one molecular alteration in the four markers. The probability of response was 51% (22/43) among patients with no alterations, 4% (2/47) among patients with 1 alteration, and 0% (0/24) for patients with ≥ 2 alterations (p&lt;0.0001). Accordingly, PFS and OS were increasingly worse for patients with tumors harboring none, or ≥ 2 molecular alteration(s) (p&lt;0.001).
When expression of PTEN and mutations of KRAS, BRAF and PIK3CA were concomitantly ascertained, up to 70% of mCRC patients unlikely to respond to anti-EGFR therapies can be identified. We propose to define as ‘quadruple negative’, the CRCs lacking alterations in KRAS, BRAF, PTEN and PIK3CA. The functional role of mutated KRAS, BRAF and PIK3CA alleles in modulating resistance to cetuximab was evaluated in multiple cellular models in the presence or absence of ligands of the EGF receptor. The introduction of these oncogenic alleles in colorectal cancer cells impaired the therapeutic effect of cetuximab. Accordingly, we propose a molecular mechanism whereby the occurrence of KRAS and BRAF mutations together with the availability of EGF receptor ligands modulate the response to anti EGFR monoclonal antibodies.
Comprehensive molecular dissection of the EGFR signaling pathways should be considered to select mCRC patients for cetuximab- or panitumumab based therapies. The rapid and effective translation of these findings into predictive biomarkers to couple EGFR-targeted antibodies to the patients that benefit from them represent a paradigm of modern clinical oncology.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B229.