Therapeutic implications of resistance to molecular therapies in metastatic colorectal cancer.
Metastatic colorectal cancer (mCRC) patients carrying KRAS mutated tumors do not benefit from epidermal growth factor receptor (EGFR)-targeted cetuximab- or panitumumab-based therapies. Indeed, the mutational status of KRAS is currently a validated predictive biomarker employed to select mCRC patients for EGFR targeted drugs. When patients fail standard 5-fluorouracil-, oxaliplatin-, irinotecan- and bevacizumab-based therapies, EGFR-targeted salvage therapy can be prescribed only for those individuals with KRAS wild-type cancer. Thus, clinicians are now facing the urgent issue of better understanding the biology of KRAS mutant disease, in order to devise novel effective therapies in such defined genetic setting. In addition to KRAS, recent data point out that BRAF and PIK3CA exon 20 mutations hamper response to EGFR-targeted treatment in mCRC, potentially excluding from treatment also patients with these molecular alterations in their tumor. This review will focus on current knowledge regarding the molecular landscape of mCRC including and beyond KRAS, and will summarize novel rationally-developed combinatorial regimens that are being evaluated in early clinical trials.
The Falck Division of Medical Oncology, Department of Oncology, Ospedale Niguarda Ca'Granda, Piazza Ospedale Maggiore 3, Milan, Italy. andrea.sartorebianchi@ospedaleniguarda.it
A
A
Sartore-Bianchi
K
K
Bencardino
A
A
Cassingena
F
F
Venturini
C
C
Funaioli
T
T
Cipani
A
A
Amatu
L
L
Pietrogiovanna
R
R
Schiavo
F
F
Di Nicolantonio
S
S
Artale
A
A
Bardelli
S
S
Siena
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000187:drug effects*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000032:analysis*; D016283:Proto-Oncogene Proteins p21(ras); D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D016879:Salvage Therapy; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000032:analysis*
D000911:Antibodies, Monoclonal; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D066246:ErbB Receptors; C446603:TPTE protein, human; D051059:PTEN Phosphohydrolase; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins