Table 1.
CAF-secreted soluble factors involved in resistance to targeted therapies
| CAF-secreted soluble factors | Mechanism of resistance to targeted therapies | Clinical application of inhibitors: representative agents in phase2/3 clinical trials |
|---|---|---|
| Hepatocyte Growth Factor (HGF) |
Activation of MET anti-apoptotic and pro-mitogenic downstream pathways in tumor cells Induction of stabilization/upregulation of multiple EGFR binding partners such as Axl, EphA2, CDCP1, JAK1 and integrin Beta-4 |
MET (HGFR) TKIs: Foretinib (GSK1363089) Crizotinib (PF-02341066) Cabozantinib (BMS-907351) Capmatinib (INC280) Tepotinib (EMD 1214063) HGF targeting mAbs: Rilotumumab (AMG 102) Ficlatuzumab (AV-299) L2G7 (TAK-701) |
| Fibroblast Growth Factors (FGFs) | Activation of FGF Receptors (mainly FGFR2) and their anti-apoptotic and pro-mitogenic downstream pathways in tumor cells |
Pan-FGFR TKIs: Erdafitinib (JNJ-42756493) Derazantinib (ARQ087) Rogoratinib (BAY1163877) Dovitinib (TKI258) AZD4547 Futibatinib (TAS-120) Zoligratinib (Debio-1347) Infigratinib (BGJ398) |
| Transforming Growth Factorβ (TGFβ) | Upregulation of lncRNAs, including the lncRNA HOTAIR, able to activate estrogen receptor function in the absence of estrogens |
TGFβ Receptor inhibitors: Galunisertib (LY2157299) TGFβ Receptor mAbs: Fresolimumab (GC1008) TGFβ antisense oligonucleotides: Trabedersen (AP 12009) |
| Neuregulin-1b (NRG-1b) | Increased expression of FOXA1 and HER3 in cancer cells; HER3 activation. | No inhibitors in phase 2/3 trials |
| Insulin Growth Factor 2 (IGF2) | Activation of IGF1R anti-apoptotic and pro-mitogenic downstream pathways in tumor cells |
IGF-1R TKIs: Linsitinib (OSI-906) Ceritinib (LDK378) Brigatinib (AP26113) |
| Platelet-Derived Growth Factor C (PDGF-C) | Activation of PDGFR and promotion of angiogenesis |
PDGFR-α inhibitors: Imatinib (STI571) Ponatinib (AP24534) Nintedanib (BIBF 1120) Crenolanib (CP-868596) Masitinib (AB1010) |
| IL-6 family members |
Expansion of the stem cell pool via JAK1/STAT3 signaling Activation of NF-kB and AKT pathways in cancer cells |
IL-6 targeting mAb: Siltuximab (CNTO 328) JAK1/2 inhibitors: Ruxolitinib (INC424, INCB1842) |
| Chemokine (C-X-C motif) ligand 13 (CXCL13) | Recruitment of B lymphocytes that produce pro-survival cytokines | No inhibitors in phase 2/3 trials |
| Secreted Frizzled Related Protein 2 (sFRP2) | Wnt Antagonist, Loss Of The Key Redox Effector APE1 And Attenuated Response To ROS-Induced DNA Damage | No inhibitors in phase 2/3 trials |