Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors

Abstract

Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E. We found that AXL-107-MMAE, as a single agent, displayed potent in vivo anti-tumor activity in patient-derived xenografts, including melanoma, lung, pancreas and cervical cancer. By eliminating distinct populations in heterogeneous melanoma cell pools, AXL-107-MMAE and MAPK pathway inhibitors cooperatively inhibited tumor growth. Furthermore, by inducing AXL transcription, BRAF/MEK inhibitors potentiated the efficacy of AXL-107-MMAE. These findings provide proof of concept for the premise that rationalized combinatorial targeting of distinct populations in heterogeneous tumors may improve therapeutic effect, and merit clinical validation of AXL-107-MMAE in both treatment-naive and drug-resistant cancers in mono- or combination therapy.

Detection of AXL expression in circulating tumor cells of lung cancer patients using an automated microcavity array system

“…AXL is known to be an important factor driving epithelial‐to‐mesenchymal transition (EMT) and is involved in a wide variety of cellular responses including promoting cell proliferation, survival, adhesion, motility, and invasion . Moreover, the level of AXL expression is associated with cancer progression and drug resistance, thus new pharmaceuticals targeting AXL are being developed . The detection of AXL‐expressing CTCs in peripheral blood would be useful for deciding on therapeutic strategy.…”

“…[19][20][21] Moreover, the level of AXL expression is associated with cancer progression and drug resistance, thus new pharmaceuticals targeting AXL are being developed. [22][23][24] The detection of AXL-expressing CTCs in peripheral blood would be useful for deciding on therapeutic strategy. However, AXL is known to be the driving factor in EMT and many current technologies including CellSearch rely on epithelial-specific markers, such as cytokeratin (CK), to detect CTCs, thus the down regulation of those markers due to EMT limits the detection of AXL-expressing CTCs.…”

The AP-1 complex regulates AXL expression and determines sensitivity to PI3Kα inhibition in esophagus and head and neck squamous cell carcinoma

“…This overexpression of AXL in response to therapy is not unique to these malignant diseases or to PI3K-targeting therapies, as AXL pathway activation has been reported in various cancers that developed resistance to radiotherapy, chemotherapies and EGFR inhibitors (15)(16)(17)(18)(19)(38)(39)(40). Indeed, small molecule inhibitors (such as therapies is superior to that of the monotherapies (15,40,(42)(43)(44)(45)(46)(47).…”

“…The clinical outcomes of these studies are not yet available, but pre-clinical models indicate that the efficacy of a single agent of AXL therapies can be limited by expression of other receptors like MERTK (41), while in combination, the potency is enlarged (15,40,(42)(43)(44)(45)(46)(47).…”

Drug sales confirm clinical advantage of multi‐target inhibition of drug escapes by anticancer kinase inhibitors

“…counteractive feedback loops that evade the drug modulation of a target (Avril et al, 2017;Boshuizen et al, 2018;Tao et al, 2015). These drug-escape actions can be overcome by co-inhibiting the targetassociated DEMs (Dienstmann, De Dosso, Felip, & Tabernero, 2012;Kanda et al, 2013;Karamouzis, Konstantinopoulos, & Papavassiliou, 2009;Ng et al, 2012;Poulikakos & Solit, 2011;Sawyers, 2007) using multi-target drugs (Katakami et al, 2013;Schlumberger et al, 2015) and drug combinations (Qi et al, 2011).…”