AZD8055 enhances in vivo efficacy of afatinib in chordomas

Abstract

Chordomas are primary bone tumors that arise in the cranial base, mobile spine, and sacrococcygeal region, affecting patients of all ages. Currently, there are no approved agents for chordoma patients. Here, we evaluated the anti‐tumor efficacy of small molecule inhibitors that target oncogenic pathways in chordoma, as single agents and in combination, to identify novel therapeutic approaches with the greatest translational potential. A panel of small molecule compounds was screened in vivo against patient‐derived xenograft (PDX) models of chordoma, and potentially synergistic combinations were further evaluated using chordoma cell lines and xenograft models. Among the tested agents, inhibitors of EGFR (BIBX 1382, erlotinib, and afatinib), c‐MET (crizotinib), and mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co‐inhibition of EGFR and c‐MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co‐inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, this dual inhibition completely suppressed tumor growth in vivo, showing improved tumor control. Together, these data demonstrate that individual inhibitors of EGFR, c‐MET, and mTOR pathways suppress chordoma growth both in vitro and in vivo. mTOR inhibition increased the efficacy of EGFR inhibition on chordoma growth in several preclinical models. The insights gained from our study potentially provide a novel combination therapeutic strategy for patients with chordoma. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Dramatic In Vivo Efficacy of the EZH2-Inhibitor Tazemetostat in PBRM1-Mutated Human Chordoma Xenograft

“…Animal models of human cancers, particularly for such a rare tumor as chordoma, as well as the in vivo biological and pharmacological information they can provide, remain critical components in understanding the pathophysiology of the tumor, identifying new drug therapies, and exploring resistance mechanisms to therapies. In the past, very few models as cell lines or xenografts contributed to the study of this rare tumor and to perform pharmacological assessments [24,25,32,33]. Hence, those models remained insufficient for relevant preclinical pharmacologic screenings.…”

Emerging target discovery and drug repurposing opportunities in chordoma

“…Moreover, PI3K and mTOR are regulated by receptor tyrosine kinases (RTKs), of which several appear to be activated in most chordoma tumors ( 4 ). Several studies have analyzed the activation state or effects of targeting RTKs including MET ( 47 , 48 ), IGF1R ( 49 , 50 ), and the FGFR family ( 51 ), though PDGFRβ ( 5 , 10 ) and EGFR ( 3 , 52 ) have received the most attention, primarily owing to evidence of some clinical benefit from agents targeting these RTKs ( 9 – 11 , 13 ). Since RTK mutations are not frequently seen in chordoma, these receptors are presumably activated through alternative mechanisms such as aberrant growth factor production, which may be directly regulated by brachyury ( 53 ).…”

“…The frequent activation of RTKs observed in chordoma may be related to the role of the notochord in regulating embryonic tissue patterning; in this context RTKs are thought to dictate proliferation and differentiation through the interpretation of morphogen gradients ( 54 , 55 ). Inhibitors of wild-type EGFR, such as afatinib and cetuximab, have reproducibly shown promising activity against chordoma cell lines ( 3 , 6 , 7 ) and xenograft models ( 39 , 47 ), which has motivated two Phase II clinical trials (NCT03083678 and NCT05041127). Since these strategies rely on inhibition of wild-type EGFR, it remains to be seen whether skin and gastrointestinal toxicities will limit their efficacy in the clinic ( 56 ).…”

“…In translational cancer research, PDX models have been the gold standard for preclinical drug testing because they accurately recapitulate features of the patient’s tumor ( 108 , 109 ); this has motivated the development of over two dozen chordoma PDXs by the Chordoma Foundation and others ( 47 , 105 ) that represent the anatomical, age, histopathological, and known molecular diversity of chordoma. More recently, patient-derived organoids (PDOs) have generated significant interest as functional models because they provide faithful representations of patient tumors, while improving on initiation time, cost, and efficiency scales compared to PDXs ( 110 ).…”

“…As one of the most well-validated therapeutic targets in chordoma, inhibitors of wild-type EGFR are arguably the best ‘anchors’ to initially explore in unbiased screens or rational combination studies. Indeed, combination therapy investigations with afatinib ( 47 ) or cetuximab ( 138 ) have yielded encouraging results. One interesting hypothesis involves combining cetuximab with a CDK4/6 inhibitor ( Figure 2B ).…”