Abstract C94: Heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer are sensitive to concomitant inhibition of EGFR and MEK.

Abstract

Abstract Monoclonal antibodies targeting EGFR are used in the clinic to treat KRAS wild type metastatic colorectal cancer (CRC). After an initial response, secondary resistance occurs thereby limiting the clinical benefit of these drugs. Relapsed patients have no further therapeutic options, therefore, elucidating the molecular basis of resistance is a prerequisite for the development of further lines of therapy. We took advantage from a panel of CRC cell lines sensitive to EGFR inhibition by treating with cetuximab or panitumumab until resistant derivatives emerged. The resistant populations were heterogeneous mixture of cells bearing different alterations in KRAS, NRAS and BRAF genes at various frequencies. An RNA interference (siRNA) genetic screening unveiled that suppression of MEK1/2 together with silencing of EGFR was effective in impairing the growth of the resistant cells. Combinatorial treatment with pimasertib, a selective allosteric MEK inhibitor, together with cetuximab re-sensitizes anti-EGFR resistant derivatives despite the genetic alterations heterogeneity. Combinatorial treatment was effective in vitro and in vivo both in cell derived xenografts and in an acquired resistant patient derived xenograft (xenopatient). These observations provide a rational strategy to overcome the multifaceted clonal heterogeneity that emerges when tumors are treated with targeted agents. We propose that MEK inhibitors, in combination with cetuximab or panitumumab, should be tested in clinical trials in CRC patients who become refractory to anti-EGFR therapies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C94. Citation Format: Sandra Misale, Sabrina Arena, Simona Lamba, Giulia Siravegna, Alice Lallo, Sebastijan Hobor, Mariangela Russo, Michela Buscarino, Andrea Sartore-Bianchi, Katia Bencardino, Alessio Amatu, Salvatore Siena, Federica Di Nicolantonio, Alberto Bardelli. Heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer are sensitive to concomitant inhibition of EGFR and MEK. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C94.