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

February 1, 2018

For dose-response curves and viability assays in melanoma, 1 × 103 cells were plated in 96-well plates and ADC was added 3 h after seeding with the HP D300 Digital Dispenser (Tecan)

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.

Boshuizen, J; Koopman, LA; Krijgsman, O; Shahrabi, A; van den Heuvel, EG; Ligtenberg, MA; Vredevoogd, DW; Kemper, K; Kuilman, T; Song, JY; Pencheva, N; Mortensen, JT; Foppen, MG; Rozeman, EA; Blank, CU; Janmaat, ML; Satijn, D; Breij, ECW; Peeper, DS; Parren, PWHI;

Journal: Nat. Med. Pages: 203-212

Original article (29334371)