Abstract
BackgroundThe development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms.MethodsWe analyzed 21 KRAS, NRAS, BRAF, and PI3K wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways.ResultsIn vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies.ConclusionsOur study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC.
Highlights
The development of secondary resistance (SR) in metastatic colorectal cancer treated with anti-epidermal growth factor receptor antibodies is not fully understood at the molecular level
Our study demonstrates that SR patient-derived xenograft (PDX) tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient
It suggests that the development of anti-epidermal growth factor receptor (EGFR) tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in colorectal cancer (CRC) is likely more prevalent than previously anticipated
Summary
The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. The emergence of RAS mutations in ctDNA at the time of disease progression in patients undergoing anti-EGFR therapy was reported to be neither associated with a shorter progression-free survival nor predictive for any cytoreduction [8, 19] This suggests that as tumors undergo clonal expansion in response to targeted therapy, not every mutation identified in ctDNA may be driving SR and that other molecular mechanisms may play a role in acquiring resistance to anti-EGFR antibodies. Mathematical modeling of the dynamic of resistance development in PDXs under vertical blockade of the EGFR pathway by Misale et al concluded that their data supported a model which beyond point mutations in driver genes other non-genetic or genetic mechanisms are required to achieve the high number of cetuximab-resistant cells at the start of treatment [10]
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