Abstract 1843: Primary and acquired resistance to HERs inhibition in colorectal cancer cells: All HERs go to RAS

Abstract

Abstract The monoclonal antibodies cetuximab and panitumumab are approved for the treatment of metastatic colorectal cancers (mCRC). When used as monotherapy, the anti-EGFR antibodies are effective in approximately 15% of patients. It is now well established that colorectal tumors carrying KRAS and BRAF mutations (40%) are refractory to EGFR targeted therapies (primary resistance). Virtually all-responsive patients eventually become insensitive to anti-EGFR antibodies (secondary resistance) within 3 to 12 months of initiating therapy. Primary and acquired resistance therefore limits the clinical benefit of EGFR blockade in CRC patients. We postulated that concomitant inhibition of multiple members of the HER (ErbB) receptors family might suppress the growth of CRC cells more effectively than selectively targeting only the EGFR with cetuximab or panitumumab. Accordingly, we assessed the pharmacological activity of momelotinib and afatinib- two pan-HER tyrosine kinase inhibitors- in a collection of 40 CRC cell lines, which recapitulate the genetic profiles commonly detected in CRC patients. We report that primary resistance to pan-HER inhibition is associated with KRAS and BRAF mutations thus suggesting that this patients' population will unlikely benefit from momelotinib and afatinib treatments. Notably, however, pan-HER blockade was effective in a subset of KRAS/BRAF wild type CRC cell lines refractory to cetuximab and panitumumab indicating that a subgroup of patients, which do not benefit from EGFR blockade, may profit from pan-HER inhibition. To define the molecular mechanisms of acquired resistance to ErbB inhibitors, three KRAS/BRAF/NRAS wild type CRC cell models were continuously treated with cetuximab, momelotinib and afatinib, until resistant derivatives emerged. Genetic characterization of such derivatives unveiled that, regardless of the drug used, the resistant populations were a mixture of clones carrying distinctive mutations in KRAS or NRAS. Detailed biochemical analyses of the ErbB signalling pathway revealed that resistant variants displayed high levels of MEK and ERK activation, which persisted upon ErbBs inhibition. Collectively, these results identify KRAS, BRAF and NRAS mutations as major drivers of primary and/or acquired resistance to HERs inhibition in colorectal cancer cells and suggest that a molecularly defined subset of CRC patients might benefit from pan-HER blockade. Citation Format: Mariangela Russo, Alessandra Riggio, Carlotta Cancelliere, Federica Di Nicolantonio, Alberto Bardelli. Primary and acquired resistance to HERs inhibition in colorectal cancer cells: All HERs go to RAS. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1843. doi:10.1158/1538-7445.AM2014-1843