TFE3‐PD‐L1 axis is pivotal for sunitinib resistance in clear cell renal cell carcinoma

Abstract

Renal cell carcinoma (RCC) has become the most malignant tumour of kidneys in worldwide. 1 Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCCs, representing approximately 70% of all adult renal carcinomas. The other histologies mainly encompass papillary and chromophobe RCC. 2 The prognosis of ccRCC is poor: 30% of patients are metastatic at diagnosis and almost 30% of the remaining patients will develop metastasis detected during the follow-up. 3 With the continuous development of medicine, the treatment and management of ccRCC, particularly metastatic RCC, have radically changed over the past few decades. 4 Initially, first-generation immunotherapy with cytokines: interleukins or interferon represented standard approaches but with poor results. 5,6 In recent years, the development of tyrosine kinase inhibitors (TKI), mainly targeted to vascular endothelial growth factor receptor, largely improved the prognosis of both overall survival (OS) and progression free survival (PFS). 7 Sunitinib malate (Sun) is an oral multi-targeting TKI that is registered for the treatment of advanced or metastatic RCC. 8,9 Currently, the emergence of immune checkpoint inhibitors (ICI) showed promising results in RCC treatment. 10-12 Programmed cell death 1 (PD-1), programmed death ligand-1 (PD-L1)

Integrated mRNA and miRNA Transcriptomic Analyses Reveals Divergent Mechanisms of Sunitinib Resistance in Clear Cell Renal Cell Carcinoma (ccRCC)

“…We observed that the levels of miR-34a were significantly down-regulated in the resistant clones of all three cell lines. An increase in PD-L1 protein expression in response to transient sunitinib treatment has previously been reported in 786-O and A498 cell lines [17,54]. We extended these observations to the resistant clones of these cell lines, as well as to CD274 mRNA expression.…”

“…These results suggest that ccRCC patients with VHL gene mutations (>50% of patients) [57] that do not express HIF1α (~70% of ccRCC patients [58]) could have an improved response to sunitinib treatment through targeting of PD-L1 by checkpoint inhibitor antibodies such as avelumab that already has FDA-approval for combination treatment in ccRCC [59]. Consistent with this hypothesis, Guo et al demonstrated that a combination of anti-PD-L1 and sunitinib significantly reduced tumour progression in vivo [17]. Indeed, although immunotherapy targeting the PD-1/PD-L1 axis shows great promise for ccRCC, only 15-25% of patients respond when given it as a monotherapy [60], and there is increasing movement towards combination therapy of antiangiogenic agents and immunotherapy [59,[61][62][63][64].…”

“…Although many publications have investigated the molecular basis of sunitinib resistance [14][15][16][17][18][19], and several have considered the role of microRNAs (miRNAs) [20][21][22][23][24][25][26][27], only a few have taken an integrated genomic approach to identify miRNA-target gene interactions that can give functional insights into resistance mechanisms [28,29]. Therefore, we used generated multiple sunitinib-resistant clones in primary tumour ccRCC cell lines that are VHL-defective (786-O and A498) and the metastatic, VHL-functional, Caki-1 cell line.…”

Molecular and functional characterization of reversible‐sunitinib‐tolerance state in human renal cell carcinoma

“…The sunitinib‐tolerant phenotype showed reduced inhibition of DNA synthesis under treatment, compared to the wild‐type confirming the activity of sunitinib on cell proliferation 36,37 . In various tumour entities, aberrant activation of MET and AXL has been described in terms of resistance to RAS–RAF–MEK, mammalian target of rapamycin (mTOR), VEGFR therapies 16,38,39 including sunitinib and sorafenib, 16,40 and, recently, immune evasion 41 . The activity of c‐MET‐downstream kinases, ERK ½, and AKT/S6K might also be related to enhanced cell survival and proliferation in 786‐O/S and Caki‐2/S cells, as previous studies have reported, 42 also concerning pathogenesis and sunitinib resistance in RCC 43–45 .…”

“… 36 , 37 In various tumour entities, aberrant activation of MET and AXL has been described in terms of resistance to RAS–RAF–MEK, mammalian target of rapamycin (mTOR), VEGFR therapies 16 , 38 , 39 including sunitinib and sorafenib, 16 , 40 and, recently, immune evasion. 41 The activity of c‐MET‐downstream kinases, ERK ½, and AKT/S6K might also be related to enhanced cell survival and proliferation in 786‐O/S and Caki‐2/S cells, as previous studies have reported, 42 also concerning pathogenesis and sunitinib resistance in RCC. 43 , 44 , 45 A distinct ability to overcome cell death is a further trait of sunitinib tolerance.…”