Crosstalk between the IGF1 and CXCL12 Pathways Defines Objective Responses to the Farnesyl Transferase Inhibitor Tipifarnib in AML and PTCL Patients

Background

CXCL12 is a chemokine that is essential for the maturation of myeloid and lymphoid cells. Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). Treatment with this agent may translate to durable responses in subsets of patients (pts) with acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML) and peripheral T-cell lymphoma (PTCL) but its mechanism of action in these indications is poorly understood. We have previously reported that tipifarnib interferes with the CXCL12 pathway. Here we show that an interplay between the CXCL12 and IGF1 pathways may define those pts who may experience objective responses with tipifarnib monotherapy.

Methods

Gene expression profile (GEP) data generated using RNA-Seq and the Affymetrix U133A gene-chips of tumor samples from 129 pts enrolled into tipifarnib trials (CTEP-20, KO-TIP-002,KO-TIP-004, INT-17) were analyzed with respect to study outcomes and complemented with analyses of mRNA expression in data sets from the cBioportal for Cancer Genomics. Gene expression was further validated using RT-PCR assays. RNA-Seq and Whole Exome Sequencing were conducted using standard methodologies. Clinical trial information: NCT00027872, NCT02464228. NCT02807272, NCT00354146.

Results

In order to improve our understanding of the molecular pathology of tumor CXCL12 overexpression, we investigated GEPs from 8,401 cancer pts in 25 studies available at cBioportal (TCGA, Provisional). Notably, we found a highly significant correlation in the expression of the IGF1 and CXCL12 genes in 19 of those studies. Intriguingly, the highest IGF1/CXCL12 correlations were observed in indications, including AML (ρ=0.698, p<0.001), in which activity of tipifarnib as monotherapy has been previously reported (AML, breast and urothelial cancer). Based on these results, we investigated the effect of IGF1/CXCL12 co-expression on pt outcome in tipifarnib studies. In previously untreated AML, 3 subsets of pts were identified with respect to bone marrow (BM) IGF1/CXCL12 expression: (1) high IGF1, high CXCL12 with predominantly hematological improvement or stable disease (SD) as best response, (2) intermediate IGF1, low CXCL12, with predominantly disease progression (PD), and (3) low IGF1, variable CXCL12, with 6 complete responses in 15 pts that were associated with CXCL12 expression (p=0.013), supporting the notion that CXCL12 pathway activation determines objective responses with tipifarnib while IGF1 mediates drug resistance. Barely detectable levels of IGF1 (and IGF2) were observed in the BMs of CMML pts in whom only 1 best response of PD was reported. In contrast, elevated levels of both CXCL12 and IGF1 were observed in PTCL pts responding to tipifarnib. Further investigation revealed that tumors of PTCL pts experiencing a partial response (PR) with tipifarnib expressed high levels of IGFBP7 (p=0.03), a natural inhibitor of the IGF1 receptor. Sequencing of the CXCL12 and IGF1 genes in PTCL samples revealed the presence of polymorphisms in non-responding pts: 8 pts, 7 carrying CXCL12 rs2839695 and 1 with a novel 3UTR variant, experienced a best response of PD. No pts with a best response of PR or SD carried 3UTR variants in CXCL12 (0% vs 80%, p=0.007). No pt with a best response of PR, 1 of 4 pts with SD and 6 of 10 pts with PD carried the IGFBP7 variant L11F (rs11573021) (16% PR/SD vs 60% PD, p=0.15)

Conclusions

Pre-treatment tumor CXCL12, IGF1 and IGFBP7 expression may enable the identification of pts susceptible to experience objective responses with tipifarnib monotherapy. These data may contribute to the understanding of the mechanism of action of FT inhibitors.