Abstract
BRAFV600E mutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF–MEK–EGFR co-targeting, we used a high-throughput kinase activity mapping platform. Here we show that SRC kinases are systematically activated in BRAFV600E CRC following targeted inhibition of BRAF ± EGFR and that coordinated targeting of SRC with BRAF ± EGFR increases treatment efficacy in vitro and in vivo. SRC drives resistance to BRAF ± EGFR targeted therapy independently of ERK signaling by inducing transcriptional reprogramming through β-catenin (CTNNB1). The EGFR-independent compensatory activation of SRC kinases is mediated by an autocrine prostaglandin E2 loop that can be blocked with cyclooxygenase-2 (COX2) inhibitors. Co-targeting of COX2 with BRAF + EGFR promotes durable suppression of tumor growth in patient-derived tumor xenograft models. COX2 inhibition represents a drug-repurposing strategy to overcome therapeutic resistance in BRAFV600E CRC.
| Original language | English |
|---|---|
| Pages (from-to) | 240-256 |
| Number of pages | 17 |
| Journal | Nature Cancer |
| Volume | 4 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 9 Feb 2023 |
Bibliographical note
Funding Information:We thank E. Chow, at the Center for Advanced Technologies, UCSF, and M. Mori for support in setting up the HT-KAM liquid assay automation; J. Malato, D. Wang, P. Phojanakong, V. Steri and D. Banerji for their technical assistance with in vivo mouse studies; and J. Bolen and M. Nasser for providing details of IHC automation protocols, as well as the UCSF HDFCCC Histology and Biomarker Core for methods support. We thank Amgen for providing panitumumab. This work was supported by the following funding: the Ramon Areces Fellowship (to A.R.-S.), Natural Science Foundation of China grant no. 81001183 (to B.P.), the Dutch Cancer Society (KWF) through the Oncode Institute (to R.B.), a Marcus Program in Precision Medicine Innovation Award (to J.-P.C., C.E.A. and K.S.), MSCA grant no. 882247 (to D.S.S.), the Angela and Shu Kai Chan Endowed chair (to L.J.v.‘tV.), NIH R01CA122216 (to M.M.M.), NIH UL1TR000005, the Sigma-Aldrich/UCSF T1 Catalyst Award (to J.-P.C.) and NIH R01CA229447 (to C.E.A. and J.-P.C.).
Funding Information:
We thank E. Chow, at the Center for Advanced Technologies, UCSF, and M. Mori for support in setting up the HT-KAM liquid assay automation; J. Malato, D. Wang, P. Phojanakong, V. Steri and D. Banerji for their technical assistance with in vivo mouse studies; and J. Bolen and M. Nasser for providing details of IHC automation protocols, as well as the UCSF HDFCCC Histology and Biomarker Core for methods support. We thank Amgen for providing panitumumab. This work was supported by the following funding: the Ramon Areces Fellowship (to A.R.-S.), Natural Science Foundation of China grant no. 81001183 (to B.P.), the Dutch Cancer Society (KWF) through the Oncode Institute (to R.B.), a Marcus Program in Precision Medicine Innovation Award (to J.-P.C., C.E.A. and K.S.), MSCA grant no. 882247 (to D.S.S.), the Angela and Shu Kai Chan Endowed chair (to L.J.v.‘tV.), NIH R01CA122216 (to M.M.M.), NIH UL1TR000005, the Sigma-Aldrich/UCSF T1 Catalyst Award (to J.-P.C.) and NIH R01CA229447 (to C.E.A. and J.-P.C.).
Publisher Copyright:
© 2023, The Author(s).
