Preclinical drug testing and clinical trial planning of palbociclib (CDK4/6 inhibitor) drug combination with a PI3K or MAPK inhibitor for colorectal cancer (CRC)
Authors: C.L. Lee, S. Toomey, A. Farrelly, B. Hennessy
Journal: Annals of Oncology (2019)

Background: 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. Methods: 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. Results:Table 19PCommon 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 reachedCellsDrug CombinationsCICaCo2 Wild-TypeP+PD P+G0.6 0.3DLD1 KRAS(G13D); PIK3CA(E545K)P+PD P+G0.1 0.6LS411N BRAFV600EP+PD P+GNR 1.0SNUC4 P1K3CA(E545G)P+PD P+G0.5 0.5LS1034 KRAS(A146T)P+PD P+G0.3 0.1 Open table in a new tab All cells lines were sensitive to PD (IC50 ranges: LS1034=13nM; SNUC4=14nM; LS411N=0.001µM; CaCo2=4µM; DLD1=13µM). LS1034 was resistant to G (7.2µM), while other cells were sensitive (IC50 ranges: LS411N=76nM, DLD1=183nM; SNUC4=400nM and CaCo2=1.2µM). CaCo2, DLD1 and LS1034 were resistant to P (IC50 >15µM), whereas both LS411N (0.8µM) and SNUC4 (1.7µM) were sensitive. When tested in combination, P+G has a synergistic response in all CRC cells lines, except for LS411N which harboured BRAFV600E mutation. P+G combination is very synergistic in LS1034 with KRAS mutation. P+G combination is also synergistic in DLD1 which has KRAS and co-occurring PI3KCA mutations. The P+PD combination is also synergistic in all cells lines except for LS411N. In SNUC4 with P1K3CA mutation, both combinations demonstrated synergistic CI effects. Conclusions: 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. Legal entity responsible for the study: Oncology Molecular Medicine, Royal College of Surgeons in Ireland (RCSI), Dublin. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.