Common mutations arise from MAPK and PI3K pathways are RAS, BRAF and PIK3CA. These mutations are focus for targeted inhibitors but also serve as integrators to drug resistance occurrence. Activated MAPK signaling will co-activate PI3K pathway which serves as by-pass mechanisms for drug resistance development. Many studies demonstrated that dual-inhibition of both pathways is a better strategy to overcome drug resistance. Our research investigates this rationale and tests if palbociclib (P; CDK4/6 inhibitor) can act synergistically with either gedatolisib (G; P13K/mTOR dual inhibitors) or PD0325901 (PD; MEK 1/2 selective inhibitor) to offer a highly potent antitumour efficacy in mutant CRC cell lines.
Five human CRC cells lines were profiled for mutations using Agena Massarray. The antiproliferative response to P, G and PD alone and in combination was assessed in each cell line. Finally, IC50 and combination indexes at effective dose 50 (CI) were calculated using CalcuSyn.
Common mutations identified in each cell line and corresponding CI values for both drug combinations. The CI values <0.9 are synergistic, whereas CI values >1.0 are antagonistic. P+PD=palbociclib/PD0325901; P+G=palbociclib/gedatolisib; NR=not reachedCells Drug Combinations CI CaCo2 Wild-Type P+PD P+G 0.6 0.3 DLD1 KRAS(G13D); PIK3CA(E545K) P+PD P+G 0.1 0.6 LS411N BRAFV600E P+PD P+G NR 1.0 SNUC4 P1K3CA(E545G) P+PD P+G 0.5 0.5 LS1034 KRAS(A146T) P+PD P+G 0.3 0.1
Drug combination P+G has clear synergistic antiproliferative effect in CRC cell lines with common mutations arising from MAPK & P13K pathways except for BRAFV600E. Combination P+G is also a potential option in CRC cells harbouring KRAS with(out) activating PIK3CA mutation, which associated with MEK inhibitor resistance. Our invitro data provide good rationale for further invivo evaluation and potential clinical drug development of P+G combination as future beneficial therapy in patients with treatment-resistant colorectal cancers.
Oncology Molecular Medicine, Royal College of Surgeons in Ireland (RCSI), Dublin.
Has not received any funding.
All authors have declared no conflicts of interest.