Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

Russo, Mariangela; Misale, Sandra; Ge, Wei; Siravegna, Giulia; Crisafulli, Giovanni; Lazzari, Luca; Corti, Giorgio; Rospo, Giuseppe; Novara, Luca; Mussolin, Benedetta; Bartolini, Alice; Cam, Nicholas; Patel, Roopal; Yan, Shunqi; Shoemaker, Robert; Wild, Robert A.; Nicolantonio, Federica Di; Sartore-Bianchi, Andrea; Li, Gang; Siena, Salvatore; Bardelli, Alberto

doi:10.1158/2159-8290.cd-15-0940

Cited by 261 publications

(285 citation statements)

References 28 publications

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“…When considering TrkA as a target for cancer treatment, clinical data have emerged on resistance mutants from the pan-Trk inhibitor, Entrectinib. Russo et al have recently identified two mutations arising from Entrectinib treatment in colorectal cancers, G595R and G667C (32). G595 is in the active site and has the greater effect of the two mutations when tested individually.…”

Section: Discussionmentioning

confidence: 99%

Structural characterization of nonactive site, TrkA-selective kinase inhibitors

Su¹,

Rickert

Burlein

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosinrelated kinase A (TrkA) is linked to pain and elevated levels of NGF (the ligand for TrkA) are associated with chronic pain. Antibodies that block TrkA interaction with its ligand, NGF, are in clinical trials for pain relief. Here, we describe the identification of TrkA-specific inhibitors and the structural basis for their selectivity over other Trk family kinases. The X-ray structures reveal a binding site outside the kinase active site that uses residues from the kinase domain and the juxtamembrane region. Three modes of binding with the juxtamembrane region are characterized through a series of ligand-bound complexes. The structures indicate a critical pharmacophore on the compounds that leads to the distinct binding modes. The mode of interaction can allow TrkA selectivity over TrkB and TrkC or promiscuous, pan-Trk inhibition. This finding highlights the difficulty in characterizing the structure-activity relationship of a chemical series in the absence of structural information because of substantial differences in the interacting residues. These structures illustrate the flexibility of binding to sequences outside of-but adjacent to-the kinase domain of TrkA. This knowledge allows development of compounds with specificity for TrkA or the family of Trk proteins.TrkA | kinase | pain | inhibition | selectivity

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Section: Discussionmentioning

confidence: 99%

Structural characterization of nonactive site, TrkA-selective kinase inhibitors

Su¹,

Rickert

Burlein

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Although EGFR EC mutations can disrupt cetuximab and panitumumab binding, newer generations of therapeutic antibodies have shown promise in overcoming this resistance and may be effective in CRC patients with these alterations [45]. Although less common (0.4% overall), chromosomal rearrangements involving ALK, RET, and NTRK1 in CRC are emerging as sensitive to appropriate targeted therapies [46][47][48]. Interestingly, rearrangements were mutually exclusive from RAS/RAF alterations in 88% of cases (14 of 16), possibly suggesting an oncogene-driven, biologically distinct subset of CRC requiring further investigation.…”

Section: Discussionmentioning

confidence: 99%

Broad Detection of Alterations Predicted to Confer Lack of Benefit From EGFR Antibodies or Sensitivity to Targeted Therapy in Advanced Colorectal Cancer

Rankin¹,

Klempner

Erlich³

et al. 2016

The Oncologist

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Introduction. A KRAS mutation represented the first genomic biomarker to predict lack of benefit from anti‐epidermal growth factor receptor (EGFR) antibody therapy in advanced colorectal cancer (CRC). Expanded RAS testing has further refined the treatment approach, but understanding of genomic alterations underlying primary and acquired resistance is limited and further study is needed. Materials and Methods. We prospectively analyzed 4,422 clinical samples from patients with advanced CRC, using hybrid‐capture based comprehensive genomic profiling (CGP) at the request of the individual treating physicians. Comparison with prior molecular testing results, when available, was performed to assess concordance. Results. We identified a RAS/RAF pathway mutation or amplification in 62% of cases, including samples harboring KRAS mutations outside of the codon 12/13 hotspot region in 6.4% of cases. Among cases with KRAS non‐codon 12/13 alterations for which prior test results were available, 79 of 90 (88%) were not identified by focused testing. Of 1,644 RAS/RAF wild‐type cases analyzed by CGP, 31% harbored a genomic alteration (GA) associated with resistance to anti‐EGFR therapy in advanced CRC including mutations in PIK3CA, PTEN, EGFR, and ERBB2. We also identified other targetable GA, including novel kinase fusions, receptor tyrosine kinase amplification, activating point mutations, as well as microsatellite instability. Conclusion. Extended genomic profiling reliably detects alterations associated with lack of benefit to anti‐EGFR therapy in advanced CRC, while simultaneously identifying alterations potentially important in guiding treatment. The use of CGP during the course of clinical care allows for the refined selection of appropriate targeted therapies and clinical trials, increasing the chance of clinical benefit and avoiding therapeutic futility. Implications for Practice: Comprehensive genomic profiling (CGP) detects diverse genomic alterations associated with lack of benefit to anti‐epidermal growth factor receptor therapy in advanced colorectal cancer (CRC), as well as targetable alterations in many other genes. This includes detection of a broad spectrum of activating KRAS alterations frequently missed by focused molecular hotspot testing, as well as other RAS/RAF pathway alterations, mutations shown to disrupt antibody binding, RTK activating point mutations, amplifications, and rearrangements, and activating alterations in downstream effectors including PI3K and MEK1. The use of CGP in clinical practice is critical to guide appropriate selection of targeted therapies for patients with advanced CRC.

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“…In vitro modeling of acquired resistance in cancer cell lines has proven effective in identifying resistance mechanisms that occur clinically ( 14,15 ). From a comprehensive effort aimed at defi ning the molecular landscape of resistance to targeted therapy combinations in BRAF-mutant colorectal cancer cell lines ( 16 ), we detected the emergence of MET increased gene copy number and overexpression ( Fig.…”

Section: Overexpression or Amplifi Cation Of Met Confers Resistance Tmentioning

confidence: 99%

MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition inBRAF-Mutated Colorectal Cancer

et al. 2016

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A patient with metastatic BRAF -mutated colorectal cancer initially responded to combined EGFR and BRAF inhibition with panitumumab plus vemurafenib. Preexisting cells with increased MET gene copy number in the archival tumor tissue likely underwent clonal expansion during treatment, leading to the emergence of MET amplifi cation in the rebiopsy taken at progression. In BRAF -mutated colorectal cancer cells, ectopic expression of MET conferred resistance to panitumumab and vemurafenib, which was overcome by combining BRAF and MET inhibition. Based on tumor genotyping and functional in vitro data, the patient was treated with the dual ALK-MET inhibitor crizotinib plus vemurafenib, thus switching to dual MET and BRAF blockade, with rapid and marked effectiveness of such strategy. Although acquired resistance is a major limitation to the clinical effi cacy of anticancer agents, the identifi cation of molecular targets emerging during the fi rst treatment may afford the opportunity to design the next line of targeted therapies, maximizing patient benefi t. SIGNIFICANCE:MET amplifi cation is here identifi ed-clinically and preclinically-as a new mechanism of resistance to EGFR and BRAF dual/triple block combinations in BRAF -mutated colorectal cancer. Switching from EGFR to MET inhibition, while maintaining BRAF inhibition, resulted in clinical benefi t after the occurrence of MET-driven acquired resistance. Cancer Discov; 6(9);

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Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

Cited by 261 publications

References 28 publications

Structural characterization of nonactive site, TrkA-selective kinase inhibitors

Structural characterization of nonactive site, TrkA-selective kinase inhibitors

Broad Detection of Alterations Predicted to Confer Lack of Benefit From EGFR Antibodies or Sensitivity to Targeted Therapy in Advanced Colorectal Cancer

MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition inBRAF-Mutated Colorectal Cancer

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