Evasion Mechanisms to Igf1r Inhibition in Rhabdomyosarcoma

Abstract

Inhibition of the insulin-like growth factor 1 receptor (Igf1r) is an approach being taken in clinical trials to overcome the dismal outcome for metastatic alveolar rhabdomyosarcoma (ARMS), an aggressive muscle cancer of children and young adults. In our study, we address the potential mechanism(s) of Igf1r inhibitor resistance that might be anticipated for patients. Using a genetically engineered mouse model of ARMS, validated for active Igf1r signaling, we show that the prototypic Igf1r inhibitor NVP-AEW541 can inhibit cell growth and induce apoptosis in vitro in association with decreased Akt and Mapk phosphorylation. However, drug resistance in vivo is more common and is accompanied by Igf1r overexpression, Mapk reactivation, and Her2 overexpression. Her2 is found to form heterodimers with Igf1r in resistant primary tumor cell cultures, and stimulation with Igf2 leads to Her2 phosphorylation. The Her2 inhibitor lapatinib cooperates with NVP-AEW541 to reduce Igf1r phosphorylation and to inhibit cell growth even though lapatinib alone has little effect on growth. These results point to the potential therapeutic importance of simultaneous targeting of Igf1r and Her2 to abrogate resistance.

Cavin-1 and Caveolin-1 are both required to support cell proliferation, migration and anchorage-independent cell growth in rhabdomyosarcoma

“…104,105 Hence, it will be important to assess whether Cavin-1 and Cav-1 complexes may influence specific targets, such as p53 and IGF1R, that play a central role in RMS progression. 17,106 It is also of interest that we found Cavin-1 colocalizing with Cav-2 in proliferating RMS cells. Although we primarily focused on the interaction between Cavin-1 and Cav-1, a potential involvement of Cavin-1 and Cav-2 complexes in RMS cell survival and cancerous behavior cannot be ruled out.…”

“…The most common ERMS variant arises in children usually o5 years on distinct body sites, such as head, neck and genitourinary regions, while ARMS typically arises in the muscular limb extremities of adolescents and is characterized by poorer prognosis. 16 The genomic landscape causative of ERMS is characterized by a number of genetic lesions and/or somatic mutations that deliberately sustain the activity of different receptors, such as IGF1R, FGFR4 and Patched, [17][18][19][20][21] and related downstream pathways (i.e., RAS/ERK, PI3K/AKT and Sonic Hedgehog signaling). 11,22 In addition, defects in tumor suppressors (i.e., p53), 23 cell cycle regulatory genes (i.e., N-Myc, Rb1) 21,24 and structural proteins involved in muscular integrity (i.e., dystrophin, alpha-sarcoglycan and dysferlin) have been reported.…”

Melatonin decreases cell proliferation, impairs myogenic differentiation and triggers apoptotic cell death in rhabdomyosarcoma cell lines

“…The eRMS variant is the most treatable and most common subtype representing ~80% of RMS, while aRMS is more aggressive and characterized by a poorer prognosis. The genetic alterations characterizing eRMS commonly involve the loss of heterozygosis on chromosome region 11p15.5 (4), gain of chromosomes (5,6) and mutations on genes involved with growth factor signaling pathways (7)(8)(9)(10)(11)(12)(13)(14)(15). This leads to uncontrolled cell growth and the interruption of proper myogenic differentiation.…”

Acquired Resistance to Drugs Targeting Tyrosine Kinases

“…The same unpredictability has been seen with IGF-1R TKIs. Here, acquired resistance to NVP-AEW541 in a mouse model of metastatic alveolar rhabdomyosarcoma was caused by ERK reactivation and HER2 overexpression instead of the predicted induction of PDGFRα (Abraham et al, 2011). There is a possibility that this is caused by HER2:IGF-1R heterodimerization and receptor cross-phosphorylation by alternate ligands.…”