Table 1.
Example mechanisms of anticancer drug resistance and strategies to overcome resistance that have been proposed based on data generated by RPPA and translated to the clinical setting
| Drug class | Mechanism of resistance identified in RPPA analysis | Therapeutic strategy to overcome resistance | Clinical study | Clinical study outcome |
|---|---|---|---|---|
| PARPi | ||||
| PARPi | Increased expression and phosphorylation of S and G2/M checkpoint proteins, allowing time for repair of DNA double strand breaks | Combination treatment with PARPi and WEE1i to bypass PARPi-induced G2/M arrest |
Phase 2 trial EFFORT (NCT03579316), investigating adavosertib monotherapy and combination therapy with olaparib and adavosertib in PARPi-resistant ovarian cancer | Completed: ORR of 23% and CBR of 63% with adavosertib monotherapy; ORR of 29% and CBR of 89% with combination olaparib and adavosertib |
| Sequential treatment with PARPi and WEE1i to bypass PARPi-induced G2/M arrest and decrease toxicity of PARPi and WEE1i combination therapy | Phase 1 trial STAR (NCT04197713) investigating sequentially-dosed olaparib and adavosertib in patients with HRD-deficient solid tumors | Ongoing: Has completed does escalation phase | ||
| PARPi | Activation of the pro-survival RAS/RAF/MAPK pathway | Combination therapy with PARPi and MEKi to overcome MAPK pathway activation | Phase 1–2 trial SOLAR (NCT03162627) evaluating combination olaparib and selumetinib in solid tumors with PARPi resistance and RAS pathway alterations | Ongoing: Nearing completion |
| PARPi | Activation of the pro-survival PI3K/AKT pathway | Combination therapy with PARPi and PI3K/AKT/mTOR pathway inhibition | Phase 1 trial NCT01623349 investigating combination olaparib and alpelisib in recurrent TN breast cancer and high grade serous ovarian cancer | Completed: ORR of 33% for combination olaparib and alpelisib in patients with BRCA-wildtype platinum-resistant ovarian cancer |
| Phase 1b trial OCTOPUS (NCT02208375) investigating combination olaparib and capivasertib in breast, endometrial, and ovarian cancer | Completed: ORR of 44% for combination olaparib and capivasertib, regardless of BRCA status and platinum resistance, in endometrial cancer, and 19% across all enrolled cancer types | |||
| BRAFi | ||||
| BRAFi | Compensatory MAPK pathway hyperactivation | Intermittent dosing of combination BRAFi and MEKi to periodically remove MAPK pathway dampening and allow unchecked MAPK hyperactivation to induce apoptosis | Phase 2 trial S1320 (NCT02196181) evaluating continuous versus intermittent dosing of combination dabrafenib and trametinib in metastatic and unresectable BRAF-mutant melanoma | Completed: Poorer progression-free survival with intermittent dosing as compared to continuous dosing (5.5 versus 9.0 months) |
| BRAFi | Activation of the PI3K/AKT/mTOR pathway | Combination therapy with BRAFi and PI3K/AKT/mTOR pathway inhibition | Phase 2 trial LOGIC2 (NCT02159066) evaluating benefit of addition of buparlisib to combination encorafenib/binimetinib at time of progression | Completed: ORR 0% with addition of buparlisib |
| Phase 1 trial NCT01596140 investigating combination vemurafenib and everolimus in heavily-pretreated patients with BRAF-mutant solid tumors | Completed: ORR 22% across all enrolled patients |